Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production

ABSTRACT

This invention relates to novel lactams having the formula (I): 
                         
to their pharmaceutical compositions and to their methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to β-amyloid production such as Alzheimer&#39;s disease and Down&#39;s Syndrome.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional application of U.S. Ser. No. 11/024,377, filed Dec.28, 2004 now U.S. Pat. No. 7,112,583, and divisional application U.S.Ser. No. 10/287,117, filed Nov. 4, 2002 (U.S. Pat. No. 6,960,576, issuedNov. 1, 2005), and U.S. Ser. No. 09/805,645, filed Mar. 14, 2001 (U.S.Pat. No. 6,503,902, issued Jan. 7, 2003), which is acontinuation-in-part of U.S. Ser. No. 09/661,008, filed Sep. 13, 2000(abandoned), which claims benefit under 35 U.S.C. 119(e) of U.S.Provisional Application Nos. 60/153,511, filed Sep. 13, 1999, and60/224,388, filed Aug. 9, 2000, which disclosures are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to novel lactams having drug and bio-affectingproperties, their pharmaceutical compositions and methods of use. Thesenovel compounds inhibit the processing of amyloid precursor protein and,more specifically, inhibit the production of Aβ-peptide, thereby actingto prevent the formation of neurological deposits of amyloid protein.More particularly, the present invention relates to the treatment ofneurological disorders related to β-amyloid production such asAlzheimer's disease and Down's Syndrome.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a degenerative brain disorder characterizedclinically by progressive loss of memory, temporal and localorientation, cognition, reasoning, judgment and emotionally stability.AD is a common cause of progressive dementia in humans and is one of themajor causes of death in the United States. AD has been observed in allraces and ethnic groups worldwide, and is a major present and futurehealth problem. No treatment that effectively prevents AD or reversesthe clinical symptoms and underlying pathophysiology is currentlyavailable (for review, Dennis J. Selkoe; Cell Biology of the amyloid(beta)-protein precursor and the mechanism of Alzheimer's disease, AnnuRev Cell Biol, 1994, 10: 373-403).

Histopathological examination of brain tissue derived upon autopsy orfrom neurosurgical specimens in effected individuals revealed theoccurrence of amyloid plaques and neurofibrillar tangles in the cerebralcortex of such patients. Similar alterations were observed in patientswith Trisomy 21 (Down's syndrome), and hereditary cerebral hemorrhagewith amyloidosis of the Dutch-type. Neurofibrillar tangles arenonmembrane-bound bundles of abnormal proteinaceous filaments andbiochemical and immunochemical studies led to the conclusion that theirprinciple protein subunit is an altered phosphorylated form of the tauprotein (reviewed in Selkoe, 1994).

Biochemical and immunological studies revealed that the dominantproteinaceous component of the amyloid plaque is an approximately 4.2kilodalton (kD) protein of about 39 to 43 amino acids. This protein wasdesignated Aβ, β-amyloid peptide, and sometimes β/A4; referred to hereinas Aβ. In addition to its deposition in amyloid plaques, Aβ is alsofound in the walls of meningeal and parenchymal arterioles, smallarteries, capillaries, and sometimes, venules. Aβ was first purified anda partial amino acid reported in 1984 (Glenner and Wong, Biochem.Biophys. Res. Commun. 120: 885-890). The isolation and sequence data forthe first 28 amino acids are described in U.S. Pat. No. 4,666,829.

Compelling evidence accumulated during the last decade revealed that Aβis an internal polypeptide derived from a type 1 integral membraneprotein, termed β amyloid precursor protein (APP). β APP is normallyproduced by many cells both in vivo and in cultured cells, derived fromvarious animals and humans. Aβ is derived from cleavage of β APP by asyet unknown enzyme (protease) system(s), collectively termed secretases.

The existence of at least four proteolytic activities has beenpostulated. They include β secretase(s), generating the N-terminus ofAβ, α secretase(s) cleaving around the 16/17 peptide bond in Aβ, and γsecretases, generating C-terminal Aβ fragments ending at position 38,39, 40, 42, and 43 or generating C-terminal extended precursors whichare subsequently truncated to the above polypeptides.

Several lines of evidence suggest that abnormal accumulation of Aβ playsa key role in the pathogenesis of AD. Firstly, Aβ is the major proteinfound in amyloid plaques. Secondly, Aβ is neurotoxic and may be causallyrelated to neuronal death observed in AD patients. Thirdly, missense DNAmutations at position 717 in the 770 isoform of β APP can be found ineffected members but not unaffected members of several families with agenetically determined (familiar) form of AD. In addition, several otherβ APP mutations have been described in familiar forms of AD. Fourthly,similar neuropathological changes have been observed in transgenicanimals overexpressing mutant forms of human β APP. Fifthly, individualswith Down's syndrome have an increased gene dosage of β APP and developearly-onset AD. Taken together, these observations strongly suggest thatAβ depositions may be causally related to the AD.

It is hypothesized that inhibiting the production of Aβ will prevent andreduce neurological degeneration, by controlling the formation ofamyloid plaques, reducing neurotoxicity and, generally, mediating thepathology associated with Aβ production. One method of treatment methodswould therefore be based on drugs that inhibit the formation of Aβ invivo.

Methods of treatment could target the formation of Aβ through theenzymes involved in the proteolytic processing of β amyloid precursorprotein. Compounds that inhibit β or γsecretase activity, eitherdirectly or indirectly, could control the production of Aβ.Advantageously, compounds that specifically target γ secretases, couldcontrol the production of Aβ. Such inhibition of β or γsecretases couldthereby reduce production of Aβ, which, thereby, could reduce or preventthe neurological disorders associated with Aβ protein.

SUMMARY OF THE INVENTION

One object of the present invention is to provide novel compounds whichare useful as inhibitors of the production of Aβ protein orpharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt form or prodrugform thereof.

It is another object of the present invention to provide a method fortreating degenerative neurological disorders comprising administering toa host in need of such treatment a therapeutically effective amount ofat least one of the compounds of the present invention or apharmaceutically acceptable salt form or prodrug form thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of Formula (I):

or pharmaceutically acceptable salt form or prodrug forms thereof,wherein Q, R², R³, R⁵, R^(5a), R⁶, B, W, X, Y, and Z are defined below,are effective inhibitors of the production of Aβ.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Thus, in a first embodiment, the present invention provides a novelcompound of Formula (I):

or a pharmaceutically acceptable salt form or prodrug thereof, wherein:

-   Q is Q¹,    -   (C₁-C₃ alkyl)-O-Q¹,    -   (C₁-C₃ alkyl)-S-Q¹,    -   (C₁-C₃ alkyl)-S(═O)-Q¹,    -   (C₁-C₃ alkyl)-S(═O)₂-Q¹, or    -   (C₁-C₃ alkyl)-N(R²⁰)-Q¹;-   Q¹ is C₁-C₈ alkyl substituted with 0-3 R^(1a);    -   C₂-C₈ alkenyl substituted with 0-3 R^(1a);    -   C₂-C₈ alkynyl substituted with 0-3 R^(1a);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(1b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶, CF₃;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, C₁-C₄ haloalkyl-S—, and (C₁-C₆ alkyl)-O—C(═O)—;-   R² is H, methyl, ethyl, propyl, or butyl;-   R³ is H, C₁-C₆ alkyl, —C(═O) (C₁-C₆ alkyl), —C(═S) (C₁-C₆ alkyl), or    —C(═O)NR²¹R²²;-   alternatively, R² and OR³ are combined to form C═O or C═N—OH;-   R⁵ is H, OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3R^(5c);-   R^(5a) is H, C₁-C₄ alkyl, or C₂-C₄ alkenyl;-   alternatively, R⁵ and R^(5a) may be combined to form a 3-7 membered    cycloalkyl ring substituted with 0-3 R^(5c); optionally the    cycloalkyl ring formed by combining R⁵ and R^(5a) may be benzo    fused, wherein the benzo fused ring may be substituted with 0-3    R^(5c);-   R^(5b), at each occurrence, is independently selected from:    -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶,        acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄        haloalkyl-S—,    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁶ is H or C₁-C₆ alkyl;-   W is —(CR⁸R^(8a))_(p)—;-   p is 0, 1, 2, 3, or 4;-   R⁸ and R^(8a), at each occurrence, are independently selected from    H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈    cycloalkyl;-   X is a bond;    -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(Xb);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or    -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;-   t is 0, 1, 2, or 3;-   u is 0, 1, 2, or 3;-   R⁹ and R^(9a), at each occurrence, are independently selected from    H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,    —S(═O)₂NR^(19b)—, —C(═O)O—, or —OC(═O)—;-   Z is H;    -   C₁-C₈ alkyl substituted with 0-2 R¹²;    -   C₂-C₄ alkenyl substituted with 0-2 R¹²;    -   C₂-C₄ alkynyl substituted with 0-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   Ring B is a 6, 7, or 8 membered lactam,    -   wherein the lactam is saturated, partially saturated or        unsaturated;    -   wherein each additional lactam carbon is substituted with 0-2        R¹¹; and,    -   optionally, the lactam contains a heteroatom selected from —N═,        —NH—, —N(R¹⁰)—, —O—, —S—, —S(═O)—, and —S(═O)₂—;-   additionally, two R¹¹ substituents on adjacent atoms may be combined    to form C₃-C₆ carbocycle fused radical, a benzo fused radical, or a    5 to 6 membered heteroaryl fused radical,    -   wherein said 5 to 6 membered heteroaryl fused radical comprises        1-2 heteroatoms selected from N, O, and S;    -   wherein said benzo fused radical or 5 to 6 membered heteroaryl        fused radical is substituted with 0-3 R¹³;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,    S(═O)₂R¹⁷;    -   C₁-C₆ alkyl substituted with 0-2 R^(10a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;    -   aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is optionally substituted with 0-3        R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,    acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄    haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹¹, at each occurrence, is independently selected from H, C₁-C₄    alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,    C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(11b);-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹² at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴, at each occurrence, is independently selected from H, phenyl,    benzyl, C₁-C₆ alkyl, and C₂-C₆ alkoxyalkyl;-   R^(14a) is H, phenyl, benzyl, or C₁-C₆ alkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆    alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆    alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;-   alternatively, —NR¹⁵R¹⁶ may be a heterocyclic ring selected from the    group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,    homopiperidinyl, piperazinyl, and N-methylpiperizinyl;-   R¹⁷ is H, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl, aryl substituted by 0-4    R^(17a), or aryl-CH₂— wherein said aryl is substituted by by 0-4    R^(17a);-   R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆    alkyl)-S(═O)₂—;-   alternatively, —NR¹⁷R¹⁸ may be a heterocyclic ring selected from the    group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,    homopiperidinyl, piperazinyl, and N-methylpiperizinyl;-   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆    alkyl)-S(═O)₂—;-   R^(19b), at each occurrence, is independently selected from H and    C₁-C₆ alkyl;-   R²⁰ is H, OH, C₁-C₄ alkyl, phenyl, benzyl, or phenethyl;-   R²¹, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, and phenethyl; and-   R²², at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, and phenethyl.

[1]In another embodiment the present invention provides a compound ofFormula (I):

or a pharmaceutically acceptable salt form or prodrug thereof, wherein:

-   Q is Q¹,    -   (C₁-C₃ alkyl)-O-Q¹,    -   (C₁-C₃ alkyl)-S-Q¹,    -   (C₁-C₃ alkyl)-S(═O)-Q¹,    -   (C₁-C₃ alkyl)-S(═O)₂-Q¹ or    -   (C₁-C₃ alkyl)-N(R²⁰)-Q¹;-   Q¹ is C₁-C₈ alkyl substituted with 0-3 R^(1a);    -   C₂-C₈ alkenyl substituted with 0-3 R^(1a);    -   C₂-C₈ alkynyl substituted with 0-3 R^(1a);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(1b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶, CF₃;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, C₁-C₄ haloalkyl-S—, and (C₁-C₆ alkyl)-O—C(═O)—;-   R² is H, methyl, ethyl, propyl, or butyl;-   R³ is H, C₁-C₆ alkyl, —C(═O)(C₁-C₆ alkyl), —C(═S)(C₁-C₆ alkyl), or    —C(═O)NR²¹R²²;-   alternatively, R² and OR³ are combined to form C═O or C═N—OH;-   R⁵ is H, OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3R^(5c);-   R^(5a) is H, C₁-C₄ alkyl, or C₂-C₄ alkenyl;-   alternatively, R⁵ and R^(5a) may be combined to form a 3-7 membered    cycloalkyl ring substituted with 0-3 R^(5c);    -   optionally the cycloalkyl ring formed by combining R⁵ and R^(5a)        may be benzo fused, wherein the benzo fused ring may be        substituted with 0-3 R^(5c);-   R^(5b), at each occurrence, is independently selected from:    -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶,        acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄        haloalkyl-S—,    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁶ is H or C₁-C₆ alkyl;-   W is —(CR⁸R^(8a))_(p)—;-   p is 0, 1, 2, 3, or 4;-   R⁸ and R^(8a), at each occurrence, are independently selected from    H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈    cycloalkyl;-   X is a bond;    -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(Xb);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or    -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;-   t is 0, 1, 2, or 3;-   u is 0, 1, 2, or 3;-   R⁹ and R^(9a), at each occurrence, are independently selected from    H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,    —S(═O)₂NR^(19b)—, —C(═O)O—, or —OC(═O)—;-   Z is H;    -   C₁-C₈ alkyl substituted with 0-2 R¹²;    -   C₂-C₄ alkenyl substituted with 0-2 R¹²;    -   C₂-C₄ alkynyl substituted with 0-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   Ring B is a 6, 7, or 8 membered lactam,    -   wherein the lactam is saturated, partially saturated or        unsaturated;    -   wherein each additional lactam carbon is substituted with 0-2        R¹¹; and,    -   optionally, the lactam contains a heteroatom selected from —N═,        —N⁺(—O⁻)═, —NH—, —N(R¹⁰)—, —O—, —S—, —S(═O)—, and —S(═O)₂—;-   additionally, two R¹¹ substituents on adjacent atoms may be combined    to form C₃-C₆ carbocycle fused radical, a benzo fused radical, or a    5 to 6 membered heteroaryl fused radical,    -   wherein said 5 to 6 membered heteroaryl fused radical comprises        1-2 heteroatoms selected from N, O, and S;    -   wherein said benzo fused radical or 5 to 6 membered heteroaryl        fused radical is substituted with 0-3 R¹³;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,    S(═O)₂R¹⁷;    -   C₁-C₆ alkyl substituted with 0-2 R^(10a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;    -   aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is optionally substituted with 0-3        R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,    acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄    haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹¹ at each occurrence, is independently selected from H,    -   C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷,        C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(11b);-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, C₁-C₄ haloalkyl-S—, benzyl, benzoyl, C(═O)CH₃,    t-butoxycarbonyl, and 3,5-dimethyl-isoxazole-S(═O)₂—;-   R¹² at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴, at each occurrence, is independently selected from H, phenyl,    benzyl, C₁-C₆ alkyl, and C₂-C₆ alkoxyalkyl;-   R^(14a) is H, phenyl, benzyl, or C₁-C₆ alkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆    alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆    alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;-   alternatively, —NR¹⁵R¹⁶ may be a heterocyclic ring selected from the    group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,    homopiperidinyl, piperazinyl, and N-methylpiperizinyl;-   R¹⁷ is H, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl, aryl substituted by 0-4    R^(17a), or aryl-CH₂— wherein said aryl is substituted by by 0-4    R^(17a);-   R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆    alkyl)-S(═O)₂—;-   alternatively, —NR¹⁸R¹⁹ may be a heterocyclic ring selected from the    group: piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,    homopiperidinyl, piperazinyl, and N-methylpiperizinyl; wherein said    heterocyclic ring is substituted with 0-3 R^(11b)—;-   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆    alkyl)-S(═O)₂—;-   R^(19b), at each occurrence, is independently selected from H and    C₁-C₆ alkyl;-   R²⁰ is H, OH, C₁-C₄ alkyl, phenyl, benzyl, or phenethyl;-   R²¹, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, and phenethyl; and-   R²², at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, and phenethyl.

[2]In a preferred embodiment the present invention provides a compoundof Formula (I) wherein:

-   Q is Q¹,    -   (C₁-C₃ alkyl)-O-Q¹,    -   (C₁-C₃ alkyl)-S-Q¹,    -   (C₁-C₃ alkyl)-S(═O)-Q¹,    -   (C₁-C₃ alkyl)-S(═O)₂-Q¹, or    -   (C₁-C₃ alkyl)-N(R²⁰)-Q¹;-   Q¹ is C₁-C₆ alkyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkynyl substituted with 0-3 R^(1a);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(1b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶, CF₃;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, C₁-C₄ haloalkyl-S—, and (C₁-C₆ alkyl)-O—C(═O)—;-   R² is H, methyl, ethyl, propyl, or butyl;-   R³ is H, C₁-C₄ alkyl, —C(═O)(C₁-C₄ alkyl), —C(═S)(C₁-C₄ alkyl), or    —C(═O)NR²¹R²²;-   R⁵ is H, OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3R^(5c);-   R^(5a) is H, C₁-C₄ alkyl, or C₂-C₄ alkenyl;-   alternatively, R⁵ and R^(5a) may be combined to form a 3-7 membered    cycloalkyl ring substituted with 0-3 R^(5c);-   R^(5b), at each occurrence, is independently selected from:    -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶,        acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄        haloalkyl-S—,    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R⁶ is H, methyl, or ethyl;-   W is —(CR⁸R^(8a))_(p)—;-   p is 0, 1, or 2;-   R⁸ and R^(8a), at each occurrence, are independently selected from    H, F, methyl, and ethyl;-   X is a bond;    -   phenyl substituted with 0-3 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(Xb); or    -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;-   t is 0, 1, or 2;-   u is 0, 1, or 2;-   R⁹ and R^(9a), at each occurrence, are independently selected from    H, F, methyl, and ethyl;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —C(═O)NH—, —NHC(═O)—, —NHS(═O)₂—, or —S(═O)₂NH—;-   Z is H, halo;    -   C₁-C₄ alkyl substituted with 0-2 R¹²;    -   C₂-C₄ alkenyl substituted with 0-2 R¹²;    -   C₂-C₄ alkynyl substituted with 0-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-4 R^(12b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(12b);-   Ring B is a 7 membered lactam,    -   wherein the lactam is saturated, partially saturated or        unsaturated;    -   wherein each additional lactam carbon is substituted with 0-2        R¹¹; and,    -   optionally, the lactam contains a heteroatom selected from —N═,        —NH—, —N(R¹⁰)—, —O—, —S—, —S(═O)—, and —S(═O)₂—;-   additionally, two R¹¹ substituents on adjacent atoms may be combined    to form C₃-C₆ carbocycle fused radical, a benzo fused radical, or a    5 to 6 membered heteroaryl fused radical,    -   wherein said 5 to 6 membered heteroaryl fused radical comprises        1-2 heteroatoms selected from N, O, and S;    -   wherein said benzo fused radical or 5 to 6 membered heteroaryl        fused radical is substituted with 0-3 R¹³;-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,    S(═O)₂R¹⁷;    -   C₁-C₆ alkyl substituted with 0-2 R^(10a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or aryl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,    acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄    haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹¹, at each occurrence, is independently selected from H, C₁-C₄    alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,    C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(11b);-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹² at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴, at each occurrence, is independently selected from H, phenyl,    benzyl, C₁-C₆ alkyl, and C₂-C₆ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆    alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆    alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;-   alternatively, —NR¹⁵R¹⁶ may be a heterocyclic ring selected from the    group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,    homopiperidinyl, piperazinyl, and N-methylpiperizinyl;-   R¹⁷ is H, aryl, aryl-CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆    alkyl)-S(═O)₂—;-   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆    alkyl)-S(═O)₂—;-   alternatively, —NR¹⁷R¹⁸ may be a heterocyclic ring selected from the    group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,    homopiperidinyl, piperazinyl, and N-methylpiperizinyl;-   R²⁰ is H, OH, C₁-C₄ alkyl, phenyl, benzyl, or phenethyl;-   R²¹, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, and phenethyl; and-   R²², at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, and phenethyl.

[3]In a preferred embodiment the present invention provides a compoundof Formula (I) wherein Ring B is selected from:

wherein each benzo fused radical is substituted with 0-3 R¹³.

[4]In a preferred embodiment the present invention provides a compoundof Formula (Ia):

or a pharmaceutically acceptable salt form or prodrug thereof, wherein:

-   Q is Q¹,    -   (C₁-C₃ alkyl)-O-Q¹,    -   (C₁-C₃ alkyl)-S-Q¹,    -   (C₁-C₃ alkyl)-S(═O)-Q¹,    -   (C₁-C₃ alkyl)-S(═O)₂-Q¹ or    -   (C₁-C₃ alkyl)-N(R²⁰)-Q¹;-   Q¹ is C₁-C₆ alkyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkynyl substituted with 0-3 R^(1a);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(1b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶, CF₃;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, C₁-C₄ haloalkyl-S—, and (C₁-C₆ alkyl)-O—C(═O)—;-   R² is H, methyl, or ethyl;-   R⁵ is H, OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3R^(5c);-   R^(5a) is H, C₁-C₄ alkyl, or C₂-C₄ alkenyl;-   alternatively, R⁵ and R^(5a) may be combined to form a 3-7 membered    cycloalkyl ring substituted with 0-3 R^(5c);-   R^(5b), at each occurrence, is independently selected from:    -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶,        acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄        haloalkyl-S—,    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   W is (CR⁸R^(8a))_(p)—;-   p is 0, 1, or 2;-   R⁸ and R^(8a), at each occurrence, are independently selected from    H, F, methyl, and ethyl;-   X is a bond;    -   phenyl substituted with 0-3 R^(Xb);    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(Xb); or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;-   t is 0, 1, or 2;-   u is 0, 1, or 2;-   R⁹ and R^(9a), at each occurrence, are independently selected from    H, F, methyl, and ethyl;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —C(═O)NH—, or —NHC(═O)—;-   Z is H, halo;    -   C₁-C₄ alkyl substituted with 0-2 R¹²;    -   C₂-C₄ alkenyl substituted with 0-2 R¹²;    -   C₂-C₄ alkynyl substituted with 0-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-4 R^(12b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(12b);-   Ring B is selected from:

-   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,    S(═O)₂R¹⁷;    -   C₁-C₆ alkyl substituted with 0-2 R^(10a);    -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is optionally substituted with 0-3        R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or aryl    substituted with 0-4 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,    acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄    haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹¹, at each occurrence, is independently selected from H, C₁-C₄    alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,    C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(11b);-   R^(11a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, C₁-C₄ haloalkyl-S—, benzyl, benzoyl, C(═O)CH₃,    t-butoxycarbonyl, and 3,5-dimethyl-isoxazole-S(═O)₂—;-   R¹² at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴, at each occurrence, is independently selected from H, phenyl,    benzyl, C₁-C₆ alkyl, and C₂-C₆ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆    alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;-   R¹⁶ at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆    alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;-   alternatively, —NR¹⁵R¹⁶ may be a heterocyclic ring selected from the    group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,    homopiperidinyl, piperazinyl, and N-methylpiperizinyl;-   R¹⁷ is H, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl, aryl substituted by 0-4    R^(17a), or aryl-CH₂— wherein said aryl is substituted by by 0-4    R^(17a);-   R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆    alkyl)-S(═O)₂—;-   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆    alkyl)-S(═O)₂—;-   alternatively, —NR¹⁸R¹⁹ may be a heterocyclic ring selected from the    group: piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,    homopiperidinyl, piperazinyl, and N-methylpiperizinyl; wherein said    heterocyclic ring is substituted with 0-3 R^(11b)—; and-   R²⁰ is H, OH, C₁-C₄ alkyl, phenyl, benzyl, or phenethyl.

[5]In a preferred embodiment the present invention provides a compoundof Formula (Ia):

wherein:Ring B is selected from:

-   Q is Q¹ or (C₁-C₃ alkyl)-O-Q¹;-   Q¹ is C₁-C₆ alkyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkynyl substituted with 0-3 R^(1a);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(1b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶, CF₃;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, C₁-C₄ haloalkyl-S—, and (C₁-C₆ alkyl)-O—C(═O)—;-   R² is H, methyl, or ethyl;-   R⁵ is H, OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₆ carbocycle substituted with 0-3 R^(5c);    -   phenyl substituted with 0-3 R^(5c); or    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3R^(5c);-   R^(5a) is H, C₁-C₄ alkyl, or C₂-C₄ alkenyl;-   alternatively, R⁵ and R^(5a) may be combined to form a C₄-C₇    cycloalkyl ring;-   R^(5b), at each occurrence, is independently selected from:    -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶,        acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄        haloalkyl-S—,    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);    -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   W is —(CR⁸R^(8a))_(p)—;-   p is 0, 1, or 2;-   R⁸ and R^(8a), at each occurrence, are independently selected from    H, methyl, and ethyl;-   X is a bond;    -   phenyl substituted with 0-3 R^(Xb);    -   C₃-C₆ cyclolakyl substituted with 0-3 R^(Xb); or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—;-   t is 0, 1, or 2;-   u is 0, 1, or 2;-   R⁹ and R^(9a), at each occurrence, are independently selected from    H, F, methyl, and ethyl;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,    —NHC(═O)—, or —C(═O)NH—;-   Z is H, F, Cl, Br;    -   C₁-C₄ alkyl substituted with 0-2 R¹²;    -   C₂-C₄ alkenyl substituted with 0-2 R¹²;    -   C₂-C₄ alkynyl substituted with 0-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-4 R^(12b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(12b);-   R¹⁰ is C(═O)R¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂R¹⁷;    -   C₁-C₆ alkyl substituted with 0-2 R^(10a);    -   phenyl substituted with 0-3 R^(10b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is optionally substituted with 0-3 R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or aryl    substituted with 0-3 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,    acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄    haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹¹, at each occurrence, is independently selected from    -   H, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹,        S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(11b);-   R^(11a), at each occurrence, is independently selected from H, C₁-C₄    alkyl, OR¹⁴, Cl, F, Br, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(11b);-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, C₁-C₄ haloalkyl-S—, benzyl, benzoyl, C(═O)CH₃,    t-butoxycarbonyl, and 3,5-dimethyl-isoxazole-S(═O)₂—;-   R¹² at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴, at each occurrence, is independently selected from H, phenyl,    benzyl, C₁-C₆ alkyl, and C₂-C₆ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆    alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;-   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆    alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;-   alternatively, —NR¹⁵R¹⁶ may be a heterocyclic ring selected from the    group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,    homopiperidinyl, piperazinyl, and N-methylpiperizinyl; and-   R¹⁷ is H, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl, aryl substituted by 0-4    R^(17a), or aryl-CH₂— wherein said aryl is substituted by by 0-4    R^(17a);-   R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl;-   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆    alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆    alkyl)-S(═O)₂—;-   R¹⁹, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and-   alternatively, —NR¹⁸R¹⁹ may be a heterocyclic ring selected from the    group: piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,    homopiperidinyl, piperazinyl, and N-methylpiperizinyl; wherein said    heterocyclic ring is substituted with 0-3 R^(11b)—.

[6]In a preferred embodiment the present invention provides a compoundof Formula (Ia) wherein:

-   Q is Q¹;-   Q¹ is C₁-C₆ alkyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkynyl substituted with 0-3 R^(1a);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(1b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶, CF₃;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, C₁-C₄ haloalkyl-S—, and (C₁-C₆ alkyl)-O—C(═O)—;-   R² is H, methyl, or ethyl;-   R⁵ is H, OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b); or    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);-   R^(5a) is H, methyl, ethyl, propyl, butyl, or C₂-C₄ alkenyl;-   alternatively, R⁵ and R^(5a) may be combined to form a C₄-C₇    cycloalkyl ring;-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O,        NR¹⁵R¹⁶,    -   C₃-C₇ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₇ carbocycle substituted with 0-3 R^(5c);    -   phenyl substituted with 0-3 R^(5c); and    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂    haloalkoxy;-   W is —(CHR⁸)_(p)—;-   p is 0 or 1;-   R⁸ is H, methyl, or ethyl;-   X is a bond;    -   phenyl substituted with 0-2 R^(Xb);    -   C₅-C₆ cycloalkyl substituted with 0-3 R^(Xb); or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   Y is a bond, —V—, —CH₂—V—, —V—CH₂—, or —CH₂—V—CH₂—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —N(R¹⁹);-   Z is H, F, Cl, Br, C₁-C₄ alkyl substituted with 0-2 R¹²;    -   C₂-C₄ alkenyl substituted with 0-2 R¹²;    -   C₂-C₄ alkynyl substituted with 0-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-4 R^(12b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(12b);-   R¹⁰ is C(═O)R¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂R¹⁷;    -   C₁-C₆ alkyl substituted with 0-2 R^(10a);    -   phenyl substituted with 0-3 R^(10b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is optionally substituted with 0-3 R^(10b);-   R^(10a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or aryl    substituted with 0-3 R^(10b);-   R^(10b), at each occurrence, is independently selected from H, OH,    C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,    acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄    haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹¹, at each occurrence, is independently selected from H, ═O,    NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(11b); wherein        said 5 to 7 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl,        imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;-   R^(11a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, ═O,    NR¹⁵R¹⁶, CF₃;    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(11b); wherein        said 5 to 7 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl,        imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl,    C₁-C₂ haloalkoxy, benzyl, benzoyl, C(═O)CH₃, t-butoxycarbonyl, and    3,5-dimethyl-isoxazole-S(═O)₂—;-   R¹² at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴, at each occurrence, is independently selected from H, phenyl,    benzyl, C₁-C₄ alkyl, and C₂-C₄ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;-   R¹⁶, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl,    CH₃CH₂C(═O)—, CH₃C(═O)—, CH₃CH₂C(═O)—, CH₃C(═O)—, CH₃CH₂S(═O)₂— and    CH₃S(═O)₂—;-   R¹⁷ is H, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl; phenyl substituted by    0-2 R^(17a); or benzyl substituted by 0-2 R^(17a);-   R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl;-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;-   R¹⁹, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, and butyl; and-   alternatively, —NR¹⁸R¹⁹ may be a heterocyclic ring selected from the    group: piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,    homopiperidinyl, piperazinyl, and N-methylpiperizinyl; wherein said    heterocyclic ring is substituted with 0-3 R^(11b)—.

[7] In a preferred embodiment the present invention provides a compoundof Formula (Ia) wherein:

-   Q is Q¹,-   Q¹ is C₁-C₆ alkyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkynyl substituted with 0-3 R^(1a);    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(1b);    -   phenyl substituted with 0-3 R^(1b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(1b);-   R^(1a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, butyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶, CF₃;    -   C₃-C₆ carbocycle substituted with 0-3 R^(1b);    -   phenyl substituted with 0-3 R^(1b); and    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(1b);-   R^(1b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,    C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, (methyl)OC(═O)—, (ethyl)OC(═O)—,    (propyl)OC(═O)—, and (butyl)OC(═O)—;-   R² is H or methyl;-   R⁵ is H, OR¹⁴;    -   C₁-C₄ alkyl substituted with 0-1 R^(5b);    -   C₂-C₄ alkenyl substituted with 0-1 R^(5b); or    -   C₂-C₄ alkynyl substituted with 0-1 R^(5b);-   R^(5a) is H, methyl, ethyl, propyl, or butyl;-   alternatively, R⁵ and R^(5a) may be combined to form a cyclobutyl,    cyclopentyl, cyclohexyl, or cycloheptyl ring;-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, Cl, F, ═O, NR¹⁵R¹⁶,    -   C₃-C₇ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₇ carbocycle substituted with 0-3 R^(5c);    -   phenyl substituted with 0-3 R^(5c); and    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(5c); wherein        said 5 to 7 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl,        imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   W is a bond, —CH₂—, or —CH(CH₃)—;-   X is a bond;    -   phenyl substituted with 0-1 R^(Xb);    -   C₅-C₆ cycloalkyl substituted with 0-1 R^(Xb); or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-1 R^(Xb); wherein        said 5 to 6 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, and        isoxazolyl;-   R^(Xb), at each occurrence, is independently selected from    -   H, OH, Cl, F, Br, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,        S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,        propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   Y is a bond, —V—, —V—CH₂—, or —CH₂V—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —N(R¹⁹)—;-   Z is H, F, Cl, Br,    -   C₁-C₄ alkyl substituted with 0-2 R¹²;    -   C₂-C₄ alkenyl substituted with 0-2 R¹²;    -   C₂-C₄ alkynyl substituted with 0-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-4 R^(12b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(12b);-   R¹¹, at each occurrence, is independently selected from H, NR¹⁸R¹⁹,    CF₃;    -   C₁-C₄ alkyl substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(11b); wherein        said 5 to 7 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl,        imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;-   R^(11a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, ═O,    NR¹⁵R¹⁶, CF₃;    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(11b); wherein        said 5 to 7 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl,        imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   R¹² at each occurrence, is independently selected from H, OH, Cl, F,    Br, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂    haloalkyl, and C₁-C₂ haloalkoxy;    -   phenyl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-4 R^(12b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R¹³, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br,    CN, NR¹⁵R¹⁶, and CF₃;-   R¹⁴, at each occurrence, is independently selected from H, phenyl,    benzyl, methyl, ethyl, propyl, and butyl;-   R¹⁵, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, or butyl;-   R¹⁶, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl and, phenethyl; and-   R¹⁹, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl.

[8] In a preferred embodiment the present invention provides a compoundof Formula (Ia) wherein:

-   Q is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,    —CH₂CH₂CH₂CH₂CH₂CH₃, —CH(CH₃)₂, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂,    —CH₂C(CH₃)₃,    -   —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃,    -   —CH═CH₂, —CH₂CH═CH₂, —CH₂C(CH₃)═CH₂, —CH₂CH═C(CH₃)₂,        —CH₂CH₂CH═CH₂, —CH₂CH₂C(CH₃)═CH₂, —CH₂CH₂CH═C(CH₃)₂,        cis-CH₂CH═CH(CH₃), cis-CH₂CH₂CH═CH(CH₃), trans —CH₂CH═CH(CH₃),        trans-CH₂CH₂CH═CH(CH₃);    -   —C≡H, —CH₂C≡CH, —CH₂C≡C(CH₃),    -   cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-,        cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,        cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,        cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—,    -   phenyl-, 2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-,        4-methoxyphenyl-, 4-ethoxyphenyl-, 4-propoxyphenyl-,        phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,        (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—,        (4-Cl-phenyl) CH₂—,    -   (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,        (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—,        (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,        (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,        (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—,        (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,        (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,        (3-C₁₋₄-F-phenyl)CH₂—,    -   2-furanyl-CH₂—, 3-furanyl-CH₂—, 2-thienyl-CH₂—, 3-thienyl-CH₂—,        2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—,        1-imidazolyl-CH₂—, 2-oxazolyl-CH₂—, 4-oxazolyl-CH₂—,        5-oxazolyl-CH₂—, 3-isoxazolyl-CH₂—, 4-isoxazolyl-CH₂—,        5-isoxazolyl-CH₂—,    -   phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl) CH₂CH₂—,        (4-F-phenyl) CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—,        (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—,        (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,        (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,        (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,        (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,        (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,        (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—,        (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—;    -   furanyl-CH₂CH₂—, thienyl-CH₂CH₂—, pyridyl-CH₂CH₂—,        1-imidazolyl-CH₂CH₂—, oxazolyl-CH₂CH₂—, isoxazolyl-CH₂CH₂—,        3,5-dimethylisoxazol-4-yl-CH₂CH₂—, phenyl-propyl-;    -   benzyl-CH(NH₂)—, benzyl-CH(NHC(═O)—O-tBu)-, benzyloxy-CH₂—,        pyrrolidin-2-yl-, or 3-t-butoxycarbonylpyrrolidin-2-yl-;-   R² is H or methyl;-   R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,    —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CH₂CH₂CH₂CH₂CH₃,    —CH(CH₃) CH₂CH₂CH₃, —CH₂CH(CH₃) CH₂CH₃, —CH₂CH₂CH(CH₃)₂,    —CH(CH₂CH₃)₂,    -   —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃,    -   —CH═CH₂, —CH₂CH═CH₂, —CH₂CH₂CH═CH₂, —CH═CHCH₃,        cis-CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃), trans-CH₂CH═CH(C₆H₅),        —CH₂CH═C(CH₃)₂, cis-CH₂CH═CHCH₂CH₃, trans-CH₂CH═CHCH₂CH₃,        cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH₂CH═CH(CH₃),        trans-CH₂CH═CHCH₂(C₆H₅),    -   —C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃), —CH₂C≡C(C₆H₅), —CH₂CH₂C≡CH,        —CH₂CH₂C≡C(CH₃), —CH₂CH₂C≡C(C₆H₅), —CH₂CH₂CH₂C≡CH,        —CH₂CH₂CH₂C≡C(CH₃), —CH₂CH₂CH₂C≡C(C₆H₅),    -   cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,        cyclohexyl-CH₂—, (2-CH₃-cyclopropyl)CH₂—,        (3-CH₃-cyclobutyl)CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,        cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—,        (2-CH₃-cyclopropyl)CH₂CH₂—, (3-CH₃-cyclobutyl)CH₂CH₂—,    -   phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,        (4-F-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—, 2-furanyl-CH₂—,        3-furanyl-CH₂—, 2-thienyl-CH₂—, 3-thienyl-CH₂—, 2-pyridyl-CH₂—,        3-pyridyl-CH₂—, 4-pyridyl-CH₂—, 1-imidazolyl-CH₂—,        2-oxazolyl-CH₂—, 4-oxazolyl-CH₂—, 5-oxazolyl-CH₂—,        3-isoxazolyl-CH₂—, 4-isoxazolyl-CH₂—, 5-isoxazolyl-CH₂—,    -   phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,        (4-F-phenyl)CH₂CH₂—, furanyl-CH₂CH₂—, thienyl-CH₂CH₂—,        pyridyl-CH₂CH₂—, 1-imidazolyl-CH₂CH₂—, oxazolyl-CH₂CH₂—,        isoxazolyl-CH₂CH₂—;    -   methoxy, ethoxy, propoxy, or butoxy;-   R^(5a) is H;-   alternatively, R⁵ and R^(5a) may be combined to form cyclopentyl,    cyclohexyl, or cycloheptyl;-   W is a bond, —CH₂—, or —CH(CH₃)—;-   X is a bond;

-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, S(═O)₂—, —NH—, or —N(CH₃)—;-   Z is H, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, n-butyl,    i-butyl, s-butyl, t-butyl,    -   cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    -   phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl,        3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl,        2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl,        2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl,        2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl,        3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-C₁₋₄-F-phenyl, 2-MeO-phenyl,        3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl,        4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl,        2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl,    -   furanyl, thienyl, pyridyl, N-oxide-pyridinyl, 2-Me-pyridyl,        3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl,        1-benzimidazolyl, morpholino, N-piperinyl,    -   phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,        (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—,        (4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,        (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—,        (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,        (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,        (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—,        (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,        (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,        (3-C₁₋₄-F-phenyl)CH₂—, (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—,        (4-MeO-phenyl)CH₂—, (2-PhO-phenyl)CH₂—, (3-PhO-phenyl)CH₂—,        (4-PhO-phenyl)CH₂—, (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—,        (4-Me-phenyl)CH₂—, (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—,        4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—,        (4-CF₃O-phenyl)CH₂—, (furanyl)CH₂—, (thienyl)CH₂—,        (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—, (3-Me-pyridyl)CH₂—,        (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—, (oxazolyl)CH₂—,        (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—, (cyclopropyl)CH₂—,        (cyclobutyl)CH₂—, (cyclopentyl)CH₂—, (cyclohexyl)CH₂—,        (morpholino)CH₂—, (N-pipridinyl)CH₂—,    -   phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—,        (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—,        (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—,        (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,        (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,        (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,        (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,        (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,        (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—,        (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—,        (3-C₁₋₄-F-phenyl)CH₂CH₂—, (2-MeO-phenyl)CH₂CH₂—,        (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—,        (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—,        (4-Me-phenyl)CH₂CH₂—, (2-MeS-phenyl)CH₂CH₂—,        (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—,        (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—,        (4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—, (thienyl)CH₂CH₂—,        (pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—,        (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—,        (isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—,        (cyclopropyl)CH₂CH₂—, (cyclobutyl)CH₂CH₂—, (cyclopentyl)CH₂CH₂—,        (cyclohexyl)CH₂CH₂—, (morpholino)CH₂CH₂—, or        (N-pipridinyl)CH₂CH₂—;-   R¹¹, at each occurrence, is independently selected from H, methyl,    ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,    phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl,    cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl,    cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,    cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,    cyclohexylethyl, 2-F-phenyl-, 3-F-phenyl, 4-F-phenyl, 4-Cl-phenyl,    4-CH₃-phenyl, 4-MeO-phenyl-, 4-CF₃-phenyl, (4-F-phenyl)CH₂—,    (4-Cl-phenyl)CH₂—, (4-CH₃-phenyl)CH₂—, (4-CF₃-phenyl)CH₂—,    (4-F-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (4-CH₃-phenyl)CH₂CH₂—,    (4-CF₃-phenyl)CH₂CH₂—, pyridin-2-yl-, pyridin-3-yl-,    4-CF₃-pyridin-2-yl-, 4-CH₃-pyridin-2-yl-, thiazol-2-yl-,    azapan-1-yl, N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino,    and N,N-dibutylamino; and-   R¹³, at each occurrence, is independently selected from H, MeO, F,    and Cl.

[9] In a preferred embodiment the present invention provides a compoundof Formula of Formula (Ic);

or a pharmaceutically acceptable salt form or prodrug thereof.

[10] In a preferred embodiment the present invention provides a compoundof Formula (Id);

or a pharmaceutically acceptable salt form or prodrug thereof.

[11] In a preferred embodiment the present invention provides a compoundof Formula (Ie):

or a pharmaceutically acceptable salt form or prodrug thereof.

[12] In a preferred embodiment the present invention provides a compoundselected from:

-   3-(2    (R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2    (R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-S-(4-fluoro-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Benzyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2    (R)-Isopropyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2    (R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4-(3,5-difluorophenoxy)butyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-(3,5-difluorophenoxy)butyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7-chloro-1-methyl-5-(4-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2    (R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Benzyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Isopropyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2    (R)-Methoxy-3(S)-hydroxyl-1-oxo-4-(4-trifluoromethylbenzyloxy)butyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-(2,4-difluorobenzyloxy)butyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Vinyl-3(S)-hydroxyl-1-oxo-4-benzyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2    (R)-Methyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-3-cyclopropylpropyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R)-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-nonyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenylbutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-6-phenylhexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2    (R)-Isobutyl-3(S)-hydroxyl-1-oxo-butyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2    (R)-Isobutyl-3(S)-hydroxyl-1-oxo-octyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3-phenylpropyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-5,5-dimethyl-hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3-(4-propoxyphenyl)propyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   2-(R)-cyclopropylmethyl-3-(S)-hydroxylheptanoic acid    (2-oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl)amide;-   2(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3-(S)-hydroxypentanoic    acid (2-oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl)amide;-   4-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxybutanoic acid    (2-oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl)amide;-   2-(R)-cyclopropylmethyl-3-(S)-hydroxyheptanioc acid    (1-(5-bromo-3-pyridinyl)methyl-2-oxo-azapan-3-(S)-yl)amide;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(azapan-1-yl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-S-(3,5-difluorophenyl)-3(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(4-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-methoxyphenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-methoxyphenyl)-1-methyl-2,3-dihydro-1H-1,4-benxodiazepin-2-one;-   3-(S)-(4-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxobutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxohept-6-enyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxohept-6-enyl)amino-1-methyl-S-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-cyclopropylmethyl-S-(3,5-dimethylisoxazol-4-yl)-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-(pyridin-2-yl)-2,3-dihydro-1H-1,4    benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifouoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxo-5-(thiophen-2-yl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)₃-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3-(S)-hydroxy-1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(3-(S)-hydroxyl-2-(R)-(thiophen-2-yl)methyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-7-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-7-methoxy-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-(3,5-difluorobenzyl)-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiaxepin-2-one;-   3-(S)-(2-(R)-(furan-2-yl)methyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-benzodiazepin-2-one;-   3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxooctyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxononyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl(pyridin-2-yl))-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(40trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopentylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxobutyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-(3-butenyl)-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-(3-methylbutyl)₃-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-ethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-propyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepin-2-one;-   3-(S)-(2-(R)-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(4-(S)-amino-3-(R)-hydroxyl-2-(R)-methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(4-(S)-(tert-butoxycarbonylamino-3-(R)-hydroxyl-2-(R)-methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(3-(tert-butoxycarbonylpyrrolidin-2-(R)-yl)-3-(R)-hydroxyl-2-(R)-methyl-1-oxopropyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(3-(R)-hydroxyl-2-(R)-methyl-1-oxo-3-(pyrrolidin-2-(R)-yl)propyl)-amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(4-benzyloxy-3-(R)-hydroxyl-2-(R)-iso-propyl-1-oxobutyl-amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   2-(4-(S)-amino-3-(S)-hydroxyl-2-(S)-methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2-flourophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   2-(4-(S)-(tert-butoxycarbonylamino-3-(S)hydroxyl-2-(S)-methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(thiazol-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-cyclopropylmethyl-5-(thiazol-2-yl)-2,3-dihydro-1H-1,4benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-cyclopropylmethyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-phenoxybenzyl)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-pyridinylmethyl)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(R)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-S-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-3-(S)-methyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-phenoxybenzyl)-5-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(3-(S)-acetoxy-2-(R)-iso-butyl-1-oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(S)-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-methoxy-1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   1-(1-hydroxypentyl)cyclohexanecarboxylic    acid(5-(4-fluorophenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)amide;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxooctyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxononyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one;-   3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3-(S)-hydroxyl-1-oxopentyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one;-   2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-heptanoic acid    (2-oxo-1-(3-phenylamino-benzyl)azapan-3-(S)-yl)amide;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-cyclopentyl-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-benzyl-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-benzyl-1-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-cycloheptyl-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cycloropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-cycloheptyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-butyl-5-cycloheptyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-pyridinylmethyl)-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-pyridinylmethyl)-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-(3-pyridinylmethyl)-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-1(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(N,N-dibutylamino)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-n-butyl-5-t-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-oxo-3,3-dimethylbutyl)-5-n-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-t-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-picolyl)-5-n-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-Isobutyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-homopiperidino-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-1,3-dioxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;    and-   1-pentyrylcyclohexanecarboxylic acid    (5-(4-fluorophenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)amide.

[13] In a preferred embodiment the present invention provides a compoundof Formula (I) wherein the stereochemistry of carbon 3 in lactam ring Bis of the S configuration.

[14] In a preferred embodiment the present invention provides a compoundof Formula (I) wherein the stereochemistry of carbon 3 in lactam ring Bis of the R configuration.

[15] In a preferred embodiment the present invention provides a compoundof Formula (Ib)

wherein:Ring B is selected from:

-   Q¹ is C₁-C₆ alkyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkynyl substituted with 0-3 R^(1a);    -   C₃-C₁₀ cycloalkyl substituted with 0-3 R^(1b);    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1a), at each occurrence, is independently selected from H, C₁-C₆    alkyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶, CF₃;    -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);    -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(1b);-   R^(1b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, C₁-C₄ haloalkyl-S—, and (C₁-C₆ alkyl)-O—C(═O)—;-   R⁵ is OR¹⁴;    -   C₁-C₆ alkyl substituted with 0-3 R^(5b);    -   C₂-C₆ alkenyl substituted with 0-3 R^(5b); or    -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);-   R^(5a) is H, methyl, ethyl, propyl, butyl, or C₂-C₄ alkenyl;-   alternatively, R⁵ and R^(5a) may be combined to form a C₄-C₇    cycloalkyl ring;-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O,        NR¹⁵R¹⁶,    -   C₃-C₇ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₇ carbocycle substituted with 0-3 R^(5c);    -   phenyl substituted with 0-3 R^(5c); and    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(5c);-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂    haloalkoxy;-   W is —(CHR⁸)_(p)—;-   p is 0 or 1;-   R⁸ is H, methyl, or ethyl;-   X is a bond;    -   phenyl substituted with 0-2 R^(Xb);    -   C₅-C₆ cycloalkyl substituted with 0-3 R^(Xb); or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-2 R^(Xb);-   R^(Xb), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   Y is a bond, —V—, —CH₂—V—, —V—CH₂—, or —CH₂—V—CH₂—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —N(R¹⁹)—;-   Z is H, F, Cl, Br,    -   C₁-C₄ alkyl substituted with 0-2 R¹²;    -   C₂-C₄ alkenyl substituted with 0-2 R¹²;    -   C₂-C₄ alkynyl substituted with 0-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-4 R^(12b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(12b);-   R¹¹, at each occurrence, is independently selected from H, ═O,    NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;    -   C₁-C₆ alkyl substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(11b); wherein        said 5 to 7 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl,        imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;-   R^(11a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, ═O,    NR¹⁵R¹⁶, CF₃;    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(11b); wherein        said 5 to 7 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl,        imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;-   R^(11b) at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   R¹² at each occurrence, is independently selected from H, OH, Cl, F,    Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or    -   5 to 10 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to        10 membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, and C₁-C₄ haloalkyl-S—;-   R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆    alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;-   R¹⁴, at each occurrence, is independently selected from H, phenyl,    benzyl, C₁-C₄ alkyl, and C₂-C₄ alkoxyalkyl;-   R¹⁵, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;-   R¹⁶, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl,    CH₃CH₂C(═O)—, CH₃C(═O)—, CH₃CH₂C(═O)—, CH₃OC(═O)—, CH₃CH₂S(═O)₂— and    CH₃S(═O)₂—;-   R¹⁷ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl;-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and-   R¹⁹, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, and butyl.

[16] In a preferred embodiment the present invention provides a compoundof Formula (Ib):

-   Q¹ is C₁-C₆ alkyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkenyl substituted with 0-3 R^(1a);    -   C₂-C₆ alkynyl substituted with 0-3 R^(1a);    -   C₃-C₆ cycloalkyl substituted with 0-3 R^(1b);    -   phenyl substituted with 0-3 R^(1b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(1b);-   R^(1a), at each occurrence, is independently selected from    -   H, methyl, ethyl, propyl, butyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶,        CF₃;    -   C₃-C₆ carbocycle substituted with 0-3 R^(1b);    -   phenyl substituted with 0-3 R^(1b); and    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(1b);-   R^(1b), at each occurrence, is independently selected from H, OH,    Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,    S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,    C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, (methyl)OC(═O)—, (ethyl)OC(═O)—,    (propyl)OC(═O)—, and (butyl)OC(═O)—;-   R⁵ is OR¹⁴;    -   C₁-C₄ alkyl substituted with 0-1 R^(5b);    -   C₂-C₄ alkenyl substituted with 0-1 R^(5b); or    -   C₂-C₄ alkynyl substituted with 0-1 R^(5b);-   R^(5a) is H, methyl, ethyl, propyl, or butyl;-   alternatively, R⁵ and R^(5a) may be combined to form a cyclobutyl,    cyclopentyl, cyclohexyl, or cycloheptyl ring;-   R^(5b), at each occurrence, is independently selected from:    -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, Cl, F, ═O, NR¹⁵R¹⁶,    -   C₃-C₇ cycloalkyl substituted with 0-3 R^(5c);    -   C₃-C₇ carbocycle substituted with 0-3 R^(5c);    -   phenyl substituted with 0-3 R^(5c); and    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(5c); wherein        said 5 to 7 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl,        imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;-   R^(5c), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,    ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and    C₁-C₂ haloalkoxy;-   W is a bond, —CH₂—, or —CH(CH₃)—;-   X is a bond;    -   phenyl substituted with 0-1 R^(Xb);    -   C₅-C₆ cycloalkyl substituted with 0-1 R^(Xb); or    -   5 to 6 membered heterocycle containing 1 to 3 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-1 R^(Xb); wherein        said 5 to 6 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, and        isoxazolyl;-   R^(Xb), at each occurrence, is independently selected from    -   H, OH, Cl, F, Br, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,        S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,        propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   Y is a bond, —V—, —V—CH₂—, or —CH₂V—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —N(R¹⁹)—;-   Z is H, F, Cl, Br,    -   C₁-C₄ alkyl substituted with 0-2 R¹²;    -   C₂-C₄ alkenyl substituted with 0-2 R¹²;    -   C₂-C₄ alkynyl substituted with 0-2 R¹²;    -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-4 R^(12b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(12b);-   R¹¹, at each occurrence, is independently selected from    -   H, NR¹⁸R¹⁹, CF₃;    -   C₁-C₄ alkyl substituted with 0-1 R^(11a);    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(11b); wherein        said 5 to 7 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl,        imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;-   R^(11a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, ═O,    NR¹⁵R¹⁶, CF₃;    -   phenyl substituted with 0-3 R^(11b);    -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or    -   5 to 7 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7        membered heterocycle is substituted with 0-3 R^(11b); wherein        said 5 to 7 membered heterocycle is selected from pyridinyl,        pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,        piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl,        imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;-   R^(11b), at each occurrence, is independently selected from H, OH,    Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,    propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   R¹² at each occurrence, is independently selected from H, OH, Cl, F,    Br, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂    haloalkyl, and C₁-C₂ haloalkoxy;    -   phenyl substituted with 0-4 R^(12b);    -   C₃-C₆ carbocycle substituted with 0-4 R^(12b); or    -   5 to 6 membered heterocycle containing 1 to 4 heteroatoms        selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6        membered heterocycle is substituted with 0-3 R^(12b);-   R^(12b), at each occurrence, is independently selected from    -   H, OH, Cl, F, Br, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,        S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,        propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy;-   R¹³, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br,    CN, NR¹⁵R¹⁶, and CF₃;-   R¹⁴, at each occurrence, is independently selected from H, phenyl,    benzyl, methyl, ethyl, propyl, and butyl;-   R¹⁵, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, or butyl;-   R¹⁶, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;-   R¹⁸, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, butyl, phenyl, benzyl and, phenethyl; and-   R¹⁹, at each occurrence, is independently selected from H, OH,    methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl.

[17] In a preferred embodiment the present invention provides a compoundof Formula (Ib) wherein:

-   Q¹ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,    —CH₂CH₂CH₂CH₂CH₂CH₃, —CH(CH₃)₂, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂,    —CH₂C(CH₃)₃,    -   —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃,    -   —CH═CH₂, —CH₂CH═CH₂, —CH₂C(CH₃)═CH₂, —CH₂CH═C(CH₃)₂,        —CH₂CH₂CH═CH₂, —CH₂CH₂C(CH₃)═CH₂, —CH₂CH₂CH═C(CH₃)₂,        cis-CH₂CH═CH(CH₃), cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃),        trans-CH₂CH₂CH═CH(CH₃);    -   —C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃),    -   cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-,        cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,        cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,        cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—,    -   phenyl-, 2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-,        4-methoxyphenyl-, 4-ethoxyphenyl-, 4-propoxyphenyl-,        phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,        (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—,        (4-Cl-phenyl)CH₂—,    -   (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,        (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—,        (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,        (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,        (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—,        (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,        (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,        (3-C₁₋₄-F-phenyl)CH₂—,    -   2-furanyl-CH₂—, 3-furanyl-CH₂—, 2-thienyl-CH₂—, 3-thienyl-CH₂—,        2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—,        1-imidazolyl-CH₂—, 2-oxazolyl-CH₂—, 4-oxazolyl-CH₂—,        5-oxazolyl-CH₂—, 3-isoxazolyl-CH₂—, 4-isoxazolyl-CH₂—,        5-isoxazolyl-CH₂—,    -   phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,        (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—,        (4-Cl-phenyl) CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—,        (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—,        (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—,        (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—,        (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—,        (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—,        (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—,        (3-F-5-Cl-phenyl)CH₂CH₂—;    -   furanyl-CH₂CH₂—, thienyl-CH₂CH₂—, pyridyl-CH₂CH₂—,        1-imidazolyl-CH₂CH₂—, oxazolyl-CH₂CH₂—, isoxazolyl-CH₂CH₂—,        3,5-dimethylisoxazol-4-yl-CH₂CH₂—, phenyl-propyl-;    -   benzyl-CH(NH₂)—, benzyl-CH(NHC(═O)—O-tBu)-, benzyloxy-CH₂—,        pyrrolidin-2-yl-, or 3-t-butoxycarbonylpyrrolidin-2-yl-;-   R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,    —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CH₂CH₂CH₂CH₂CH₃,    —CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH(CH₂CH₃)₂,    -   —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃,    -   —CH═CH₂, —CH₂CH═CH₂, —CH₂CH₂CH═CH₂, —CH═CHCH₃,        cis-CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃), trans-CH₂CH═CH(C₆H₅),        —CH₂CH═C(CH₃)₂, cis-CH₂CH═CHCH₂CH₃, trans-CH₂CH═CHCH₂CH₃,        cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH₂CH═CH(CH₃),        trans-CH₂CH═CHCH₂(C₆H₅),    -   —C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃), —CH₂C≡C(C₆H₅), —CH₂CH₂C≡H,        —CH₂CH₂C≡C(CH₃), —CH₂CH₂C≡C(C₆H₅), —CH₂CH₂CH₂C≡CH,        —CH₂CH₂CH₂C≡C(CH₃), —CH₂CH₂CH₂C≡C(C₆H₅),    -   cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,        cyclohexyl-CH₂—, (2-CH₃-cyclopropyl)CH₂—,        (3-CH₃-cyclobutyl)CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,        cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—,        (2-CH₃-cyclopropyl)CH₂CH₂—, (3-CH₃-cyclobutyl)CH₂CH₂—,    -   phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,        (4-F-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—, 2-furanyl-CH₂—,        3-furanyl-CH₂—, 2-thienyl-CH₂—, 3-thienyl-CH₂—, 2-pyridyl-CH₂—,        3-pyridyl-CH₂—, 4-pyridyl-CH₂—, 1-imidazolyl-CH₂—,        2-oxazolyl-CH₂—, 4-oxazolyl-CH₂—, 5-oxazolyl-CH₂—,        3-isoxazolyl-CH₂—, 4-isoxazolyl-CH₂—, 5-isoxazolyl-CH₂—,    -   phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,        (4-F-phenyl)CH₂CH₂—, furanyl-CH₂CH₂—, thienyl-CH₂CH₂—,        pyridyl-CH₂CH₂—, 1-imidazolyl-CH₂CH₂—, oxazolyl-CH₂CH₂—,        isoxazolyl-CH₂CH₂—;    -   methoxy, ethoxy, propoxy, or butoxy;-   R^(5a) is H;-   alternatively, R⁵ and R^(5a) may be combined to form cyclopentyl,    cyclohexyl, or cycloheptyl;-   W is a bond, —CH₂—, or —CH(CH₃)—;-   X is a bond;

-   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;-   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or    —N(CH₃)—;-   Z is H, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, n-butyl,    i-butyl, s-butyl, t-butyl,    -   cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    -   phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl,        3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl,        2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl,        2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl,        2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl,        3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-C₁₋₄-F-phenyl, 2-MeO-phenyl,        3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl,        4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl,        2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl,    -   furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl,        4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl,        1-benzimidazolyl, morpholino, N-piperinyl,    -   phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,        (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—,        (4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,        (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—,        (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,        (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,        (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—,        (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,        (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,        (3-C₁₋₄-F-phenyl)CH₂—, (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—,        (4-MeO-phenyl)CH₂—, (2-PhO-phenyl)CH₂—, (3-PhO-phenyl)CH₂—,        (4-PhO-phenyl)CH₂—, (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—,        (4-Me-phenyl)CH₂—, (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—,        4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—,        (4-CF₃O-phenyl)CH₂—, (furanyl)CH₂—, (thienyl)CH₂—,        (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—, (3-Me-pyridyl)CH₂—,        (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—, (oxazolyl)CH₂—,        (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—, (cyclopropyl)CH₂—,        (cyclobutyl)CH₂—, (cyclopentyl)CH₂—, (cyclohexyl)CH₂—,        (morpholino)CH₂—, (N-pipridinyl)CH₂—,    -   phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—,        (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—,        (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—,        (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,        (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,        (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,        (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,        (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,        (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—,        (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—,        (3-C₁₋₄-F-phenyl)CH₂CH₂—, (2-MeO-phenyl)CH₂CH₂—,        (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—,        (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—,        (4-Me-phenyl)CH₂CH₂—, (2-MeS-phenyl)CH₂CH₂—,        (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—,        (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—,        (4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—, (thienyl)CH₂CH₂—,        (pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—,        (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—,        (isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—,        (cyclopropyl)CH₂CH₂—, (cyclobutyl)CH₂CH₂—, (cyclopentyl)CH₂CH₂—,        (cyclohexyl)CH₂CH₂—, (morpholino)CH₂CH₂—, or        (N-pipridinyl)CH₂CH₂—;-   R¹¹ at each occurrence, is independently selected from H, methyl,    ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,    phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl,    cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl,    cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,    cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,    cyclohexylethyl, 2-F-phenyl-, 3-F-phenyl, 4-F-phenyl, 4-Cl-phenyl,    4-CH₃-phenyl, 4-MeO-phenyl-, 4-CF₃-phenyl, (4-F-phenyl)CH₂—,    (4-Cl-phenyl)CH₂—, (4-CH₃-phenyl)CH₂—, (4-CF₃-phenyl)CH₂—,    (4-F-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (4-CH₃-phenyl)CH₂CH₂—,    (4-CF₃-phenyl)CH₂CH₂—, pyridin-2-yl-, pyridin-3-yl-,    4-CF₃-pyridin-2-yl-, 4-CH₃-pyridin-2-yl-, thiazol-2-yl-,    azapan-1-yl, N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino,    and N,N-dibutylamino; and-   R¹³, at each occurrence, is independently selected from H, MeO, F,    and Cl.

[18] In a preferred embodiment the present invention provides a compoundof Formula (If);

or a pharmaceutically acceptable salt form or prodrug thereof.

[19] In a preferred embodiment the present invention provides a compoundof Formula (Ig);

or a pharmaceutically acceptable salt form or prodrug thereof.

[20] In a preferred embodiment the present invention provides a compoundof Formula (Ih);

or a pharmaceutically acceptable salt form or prodrug thereof.

[21] In a preferred embodiment the present invention provides a compoundof Formula (Ii);

or a pharmaceutically acceptable salt form or prodrug thereof.

[22] In a preferred embodiment the present invention provides a compoundof Formula (Ij);

or a pharmaceutically acceptable salt form or prodrug thereof.

[23] In a preferred embodiment the present invention provides a compoundof Formula (Ik);

or a pharmaceutically acceptable salt form or prodrug thereof.

[24] In a preferred embodiment the present invention provides a compoundselected from:

-   (2R,3S)—N-[1-butyl-5-(methylethyl)-2-oxo(3H-benzo    [f]1,4-diazepin-3-yl)]-2-(cyclopropylmethyl)-3-hydroxyheptanamide;-   (2R,3S)-2-(cyclopropylmethyl)-3-hydroxy-N-[5-(methylethyl)-2-oxo-1-benzyl(3H-benzo    [f]1,4-diazepin-3-yl)]heptanamide;-   (2R,3S)-2-(cyclopropylmethyl)-3-hydroxy-N-{5-methyl-1-[(3-{[(4-methylphenyl)sulfonyl]amino}phenyl)-methyl]-2-oxo(3H-benzo    [f]1,4-diazepin-3-yl)}heptanamide;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-t-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   (2R,3S)-2-(cyclopropylmethyl)-3-hydroxy-N-{1-[(3-{[(4-methylphenyl)sulfonyl]amino}phenyl)methyl]-2-oxo(3H,4H,5H-benzo[f]1,4-diazaperhydroepin-3-yl)}heptanamide;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-piperizinyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   7-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(2-diethylaminoethyl)-6,7-dihydro-5H-dibenzoazepin-6-one;-   7-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(3-hydroxypropyl)-6,7-dihydro-5H-dibenzoazepin-6-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(benzyl-5-(2,2-dimethylpropyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-n-butyl-5-n-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-n-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R,S)—    (2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(2,2-dimethylpropyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   7-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-n-butyl-6,7-dihydro-5H-dibenzoazepin-6-one;-   3-(R,S)—    (2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-ethylbutyl)-5-n-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-pyrrolidin-1-yl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   7-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-benzyl-6,7-dihydro-5H-dibenzoazepin-6-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-hydroxypropyl)-5-t-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-ethoxy-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-butyl-5-(2,2-dimethylpropyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-pyridinylmethyl    N-oxide)-5-(4-trifluoromethyl)phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-pyridinylmethyl    N-oxide)-5-(4-trifluoromethyl)phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-(3-pyridinylmethyl)-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-(diethylamino)ethyl)-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-(3-pyridinylmethyl    N-oxide)-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   (2R,3S)—N-(8-bromo-1,5-dimethyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(cyclopropylmethyl)-3-hydroxyheptanamide;-   6-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1,4-dibenzyl-hexahydro-5H-1,4-diazepin-5-one;-   6-(2-(R)-cyclopropylmethyl-3-(S)-hydroxy-1-oxoheptyl)amino-4-benzyl-1-[(4-chlorophenyl)sulfonyl]-hexahydro-5H-1,4-diazepin-5-one;-   6-(2-(R)-cyclopropylmethyl-3-(S)-hydroxy-1-oxopentyl)amino-4-benzyl-1-[(4-chlorophenyl)sulfonyl]-hexahydro-5H-1,4-diazepin-5-one;-   (2R,3S)-2-(cyclopropylmethyl)-N-(1-{[3-(4-fluorophenoxy)phenyl]methyl}-2-oxo(3H,4H,5H-benzo[f]azaperhydroepin-3-yl))-3-hydroxyheptanamide;-   (2R,3S)-2-(cyclopropylmethyl)-3-hydroxy-N-[2-oxo-1-benzyl(3H,4H,5H-benzo[f]azaperhydroepin-3-yl)]heptanamide;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-benzylpiperizin-1-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-methanesulfonyl-piperazin-1-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-S-(4-acetylpiperazin-1-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-([4-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperazin-1-yl]-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   3-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-benzoylpiperazin-1-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;-   4-[3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxy-heptanoylamino)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-piperazine-1-carboxylic    acid tert-butyl ester; and-   3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-pyridinylmethyl    N-oxide)-5-(4-trifluoromethyl)phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-N-oxide.

In another preferred embodiment the present invention provides allherein disclosed embodiments with the proviso that when R⁵ and R^(5a)are not simultaneously H.

In another preferred embodiment the present invention provides allherein disclosed embodiments with the proviso that when Q is a 9membered benzofused heterocyclic group substituted by 0, 1, or 2 R^(1a),then R³ is H.

In another preferred embodiment the present invention provides allherein disclosed embodiments with the proviso that when —WXYZ is atertiary butyl group and R⁵ is either C₁-C₄ alkyl or C₂ alkenyl, then Qis not phenyl substituted by 0, 1 or 2 R^(1a).

In another preferred embodiment the present invention provides allherein disclosed embodiments with the proviso that when R⁵ is C₁-C₃alkyl, then Q is not phenyl substituted by 0, 1 or 2 R^(1a).

In another preferred embodiment the present invention provides allherein disclosed embodiments with the proviso that the moiety:

of Formula (I), et seq., is not a C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₁₀ cycloalkyl-C₁-C₄ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₄alkyl-O—C₁-C₄ alkyl, C₁-C₄ alkyl-S—C₁-C₄ alkyl, C₂-C₄ alkyl-NR²⁰—C₂-C₄alkyl, C₂-C₄ alkyl-C₆-C₁₀ aryl, C₂-C₄ alkyl-C₆-C₁₀ cycloalkyl, C₂-C₈alkenyl, C₆-C₁₀ aryl-C₁-C₄ alkyl, C₆-C₁₀ aryl-C₂-C₄-alkynyl,indol-3-yl-C₁-C₃ alkyl, and imidazol-4-yl-C₁-C₃ alkyl; where the alkylgroup is substituted with OH.

In another preferred embodiment the present invention provides allherein disclosed embodiments with the proviso that the moiety:

of Formula (I), et seq., is not a C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₁₀ cycloalkyl-C₁-C₄ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₄alkyl-O—C₁-C₄ alkyl, C₁-C₄ alkyl-S—C₁-C₄ alkyl, C₂-C₄ alkyl-NR²⁰—C₂-C₄alkyl, C₂-C₄ alkyl-C₆-C₁₀ aryl, C₂-C₄ alkyl-C₆-C₁₀ cycloalkyl, C₂-C₈alkenyl, C₆-C₁₀ aryl-C₁-C₄ alkyl, C₆-C₁₀ aryl-C₂-C₄-alkynyl,indol-3-yl-C₁-C₃ alkyl, and imidazol-4-yl-C₁-C₃ alkyl; where the alkylgroup is substituted with OH.

In a second embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier.

In a third embodiment, the present invention provides a method for thetreatment of a neurological disorder associated with β-amyloidproduction comprising administering to a host in need of such treatmenta therapeutically effective amount of a compound of Formula (I).

In a preferred embodiment the neurological disorder associated withβ-amyloid production is Alzheimer's Disease.

In a fourth embodiment, the present invention provides a method forinhibiting γ-secretase activity for the treatment of a physiologicaldisorder associated with inhibiting γ-secretase activity comprisingadministering to a host in need of such inhibition a therapeuticallyeffective amount of a compound of Formula (I) that inhibits T-secretaseactivity.

In a preferred embodiment the physiological disorder associated withinhibiting γ-secretase activity is Alzheimer's Disease.

In a fifth embodiment, the present invention provides a compound ofFormula (I) for use in therapy.

In a preferred embodiment the present invention provides a compound ofFormula (I) for use in therapy of Alzheimer's Disease.

In a sixth embodiment, the present invention provides for the use of acompound of Formula (I) for the manufacture of a medicament for thetreatment of Alzheimer's Disease.

Definitions

As used herein, the term “Aβ” denotes the protein designated Aβ,β-amyloid peptide, and sometimes β/A4, in the art. Aβ is anapproximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acidsfound in amyloid plaques, the walls of meningeal and parenchymalarterioles, small arteries, capillaries, and sometimes, venules. Theisolation and sequence data for the first 28 amino acids are describedin U.S. Pat. No. 4,666,829. The 43 amino acid sequence is:

 1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gln LysLeu Val Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31 Ile IleGly Leu Met Val Gly Gly Val Val 41 Ile Ala Thr

The term “APP”, as used herein, refers to the protein known in the artas β amyloid precursor protein. This protein is the precursor for Aβ andthrough the activity of “secretase” enzymes, as used herein, it isprocessed into Aβ. Differing secretase enzymes, known in the art, havebeen designated β secretase, generating the N-terminus of Aβ, αsecretase cleaving around the 16/17 peptide bond in Aβ, and “γsecretases”, as used herein, generating C-terminal Aβ fragments endingat position 38, 39, 40, 42, and 43 or generating C-terminal extendedprecursors which are subsequently truncated to the above polypeptides

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

When any variable (e.g., R^(1a), R^(4a), R¹³ etc.) occurs more than onetime in any constituent or formula for a compound, its definition ateach occurrence is independent of its definition at every otheroccurrence. Thus, for example, if a group is shown to be substitutedwith 0-3 R^(1a), then said group may optionally be substituted with upto three R^(1a) groups and R^(1a) at each occurrence is selectedindependently from the definition of R^(1a). Also, combinations ofsubstituents and/or variables are permissible only if such combinationsresult in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms; for example, “C₁-C₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, butare not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. Preferred “alkyl” group is “C₁-C₄alkyl” wherein methyl, ethyl, n-propyl, i-propyl, n-butyl, and i-butyl,are specifically preferred. As used herein, “C₁-C₃ alkyl”, whether aterminal substituent or a alkylene group linking two substituents, isunderstood to specifically include both branched and straight-chainmethyl, ethyl, and propyl.

As used herein, “alkenyl” or “alkenylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur in anystable point along the chain. Examples of “C₂-C₆ alkenyl” include, butare not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl,hexenyl, and the like.

As used herein, “alkynyl” or “alkynylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more carbon-carbon triple bonds which may occur in any stablepoint along the chain, such as ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, and the like.

“Alkoxy” or “alkyloxy” represents an alkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge.Examples of alkoxy include, but are not limited to, methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, ands-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, “alkylthio” or“thioalkoxy” is represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo. Unless otherwise specified, preferred halo is fluoro and chloro.“Counterion” is used to represent a small, negatively charged speciessuch as chloride, bromide, hydroxide, acetate, sulfate, and the like.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen (for example—C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkylinclude, but are not limited to, trifluoromethyl, trichloromethyl,pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl,2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl.“Haloalkoxy” is intended to mean a haloalkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge;for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy,and the like. “Halothioalkoxy” is intended to mean a haloalkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge.

“Cycloalkyl” is intended to include saturated ring groups, having thespecified number of carbon atoms. For example, “C₃-C₆ cycloalkyl”denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, “carbocycle” is intended to mean any stable 3- to7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic ortricyclic, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl,naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).Preferred example of “C₃-C₁₀ carbocycle” or “C₃-C₆ carbocycle” is C₃-C₆cycloalkyl, specifically cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

As used herein, the term “heterocycle” or “heterocyclic ring” isintended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7-to 14-membered bicyclic heterocyclic ring which is saturated partiallyunsaturated or unsaturated (aromatic), and which consists of carbonatoms and 1, 2, 3 or 4 heteroatoms, preferably 1, 2, or 3 heteroatoms,independently selected from the group consisting of N, O and S andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized. The heterocyclic ring may beattached to its pendant group at any heteroatom or carbon atom whichresults in a stable structure. The heterocyclic rings described hereinmay be substituted on carbon or on a nitrogen atom if the resultingcompound is stable. If specifically noted, a nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, homopiperidinyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, purinyl, pyranyl,pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,N-oxide-pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred5 to 10 membered heterocycles include, but are not limited to,pyridinyl, N-oxide-pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl,thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl,1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl,benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, andisoquinolinyl. Preferred 5 to 7 membered heterocycles include, but arenot limited to, pyridinyl, N-oxide-pyridinyl, pyrimidinyl, triazinyl,furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,tetrazolyl; more preferred 5 to 7 membered heterocycles include, but arenot limited to, pyridinyl, N-oxide-pyridinyl, pyrimidinyl, triazinyl,furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, homopiperidinyl,pyrazolyl, imidazolyl, and tetrazolyl. Preferred 5 to 6 memberedheterocycles include, but are not limited to, pyridinyl, pyrimidinyl,triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl;more preferred 5 to 6 membered heterocycles include, but are not limitedto, pyridinyl, N-oxide-pyridinyl, pyrimidinyl, triazinyl, furanyl,thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, andtetrazolyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

As used herein, the term “aryl”, “C₆-C₁₀ aryl” or aromatic residue, isintended to mean an aromatic moiety containing the specified number ofcarbon atoms; for example phenyl, pyridinyl or naphthyl. Unlessotherwise specified, “aryl” may be unsubstituted or substituted with 0to 3 groups selected from H, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂,N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃,CH₂CH₃, CO₂H, and CO₂CH₃.

The phrase “additional lactam carbons”, as used herein, is intended todenote the number of optional carbon atoms in the lactam ring B ofFormula (I). Formula (I*):

represents the lactam ring B of Formula (I). Additional lactam carbonsare carbons in lactam ring B other than the carbons numbered 2 and 3 inthe backbone of the formula. The additional lactam carbons may beoptionally replaced by a heteroatom selected from oxygen, nitrogen andsulfur. Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7 optional carbons,wherein one optional carbon may optionally be replaced by a heteroatom,such that the total number of members of lactam ring B, including atomsnumbered 1, 2 and 3 in the backbone, does not exceed 10. It is preferredthat the total number of atoms of lactam ring B is 6, 7 or 8; it is morepreferred that the total number of atoms of lactam ring B is seven.Examples of lactam ring B include:

but are not intended to limit the invention. Preferred examples oflactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; more preferredexamples of lactam ring B are B1, B6, B8, B9, and B13. Preferredexamples of substituent R¹⁰ or R¹¹ on lactam B are methyl, ethyl,phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluorophenyl,(4-fluorophenyl)methyl, (4-chlorophenyl)methyl, and(4-trifluorophenyl)methyl. Preferred examples of substituent R¹³ onfused rings of lactam B are methyl, fluoro, and chloro.

The compounds herein described may have asymmetric centers. Oneenantiomer of a compound of Formula (I) may display superior biologicalactivity over the opposite enantiomer. For example carbon 3 of lactamring B Formula (I″) may exist in either an S or R configuration. Thus,an R or S configuration at carbon 3 in Formula (I″) is considered partof the invention. An example of such configuration includes,

but is not intended to be limited to this example of ring B. Whenrequired, separation of the racemic material can be achieved by methodsknown in the art. Additionally, the carbon atoms to which the OH and R⁵are attached may describe chiral carbons which may display superiorbiological activity over the opposite enantiomer. For example, where Qand R⁵ are not H, then the configuration of the two centers may bedescribed as (2R,3R), (2R,3S), (2S,3R), or (2S,3S). All configurationsare considered part of the invention; however, the (2R,3S) and the(2S,3R) are preferred and the (2R,3S) is more preferred.

The phrase pharmaceutically acceptable is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

“Prodrugs” are intended to include any covalently bonded carriers whichrelease the active parent drug according to formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of formula (I) are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula (I) wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of formula (I) is administered to a mammalian subject,cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of formula (I), and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

Aldol derivatives can be prepared by the procedure of Evans (D. A. Evanset al, Org. Synth. 1990, 68, 83-90), which is outlined in Scheme 1 whereacylation of an oxazolidinone with an acid chloride provides structure2. Asymmetric aldol reaction to form 3 followed by cleavage of thechiral auxiliary yielding β-hydroxycarboxylic acid 4. Additionalexamples are found in D. A. Evans Aldrichimica Acta 1982, 15, 23-32.Alternative syntheses of structures 4 can be accomplished by the methodsof Crimmins (M. T. Crimmins et al, J. Am. Chem. Soc. 1997, 119,7883-7884), Paterson (I. Paterson et al, Org. React. 1997, 51, 1-200)and Mukaiyama (T. Mukaiyama et al, Org. React. 1994, 1-104). Anti-aldolsmay be synthesized according to: (a) A. K. Ghosh, J. Am. Chem. Soc.1996, 118, 2527-2528, or (b) S. Masamune et al., J. Am. Chem. Soc. 1997,119, 2586.

Carboxylic acids of formula 4 can be coupled to an appropriate lactamintermediate using methods commonly used in peptide syntheses, such asDCC, EDC, CDI, BOP, PyBOP, HATU, HBTU and phenyl ester mediatedcoupling, as described in A. R. Chamberlin, Chem. Rev. 1997, 97,2243-2266. Compound 6 is synthesized, as illustrated in Scheme 2, bycoupling acid 4 with 3-amino-1,4-benzodiazepin-2-one 5 under thecatalysis of EDC and HOBt providing the final compound 6 (S. Nozaki etal, Bull. Chem. Soc. Jpn. 1982, 55, 2165-2168).

Similarly, Schemes 2a and 2b illustrate synthesis of bisbenzodiazepineand lactam compounds of the present invention:

Methods for the synthesis of lactam intermediates as contemplated by thepresent invention useful in the synthesis of compounds of Formula (I),including amino benzodiazepinones, dibenzo azepinones and other relatedheterocycles, are known in the art and are disclosed in a number ofreferences including PCT publication number WO 98/28268, WO 99/66934, WO00/07995, and WO 00/38618, which are hereby incorporated by reference.Additional references include Bock, et al, J. Org. Chem., 1987, 52,3232-3239; Sherrill et al, J. Org. Chem., 1995, 60, 730-734; and Walsh,D. A., Synthesis, September 1980, p. 677; and Brown, et al., TetrahedronLetters, 1971, 8, 667-670.

Synthetic approaches to aminobenzodiazepines are widely described in theliterature and well known to one skilled in the art. The typical methodsare illustrated, but are not limited to, the following references. See(a) M. G. Bock et al., J. Org. Chem., 1987, 52, 3232; (b) R. G. Sherrillet al., J. Org. Chem., 1995, 60, 734; (c) M. G. Bock et al., J. Med.Chem., 1989, 32, 13-16; (d) J. L. Castro et al., J. Med. Chem., 1997,40, 2491-2501; (e) M. S. Chambers et al., Bioorg. & Med. Chem. Lett.,1993, 3 (10), 1919-1924; (f) J. H. Gogerty et al., J. Med. Chem., 1977,20 (7), 952; (g) G. Semple et al., Bioorg. & Med. Chem. Lett., 1996,6(1), 51-54; (h) G. Semple et al., J. Med. Chem., 1997, 40, 331-341; (i)G. Semple et al., Bioorg. & Med. Chem. Lett., 1996, 6 (1), 55-58; (j) G.Semple et al., Synth. Commun., 1996, 26 (4), 721-727; and (k) G. A.Showell et al., J. Med. Chem., 1994, 37, 719-721. For general syntheticdescriptions of 2-aminobenzophenone with various substitutions used inthe preparation of benzodiazepines, see D. A. Walsh, Synthesis 1980,677.

The preparation of aldehyde Q-CHO with general structure of 9 is shownin Scheme 3 (H. C. Arndt, Synthesis 1979, 202-204). Allyl ether 8 can bemade from the action of an alkoxide generated in DMF with allyl bromide,which is converted to α-alkoxy- or aryloxyaldehyde 9 using a two-phaseosmium tetraoxide oxidation.

As shown in Scheme 4, aldehyde Q-CHO of general structure 12 can beprepared in the same fashion from the corresponding allyl benzyl ether,which is readily available according to the procedure described by P.Kocienski (P. Kocienski Tetrahedron 1990, 46, 1767-1782).

The aldehydes used in Scheme 1 are either commercially available,prepared from commercially available or readily accessible alcohols, orprepared from commercially available or readily accessible carboxylicacids. For preparation of other non-commercially available aldehydesfrom commercially available or readily accessible alcohols by oxidationof the corresponding alcohols, see (a) S. V. Ley et al Synthesis 1994,639; (b) D. Swern, Synthesis 1981, 165-185; and (c) R. C. Larock,Comprehensive Organic Transformations, Wiley-VCH: 1989; pp 604-614. Forpreparation of other non-commercially available aldehydes fromcommercially available or readily accessible carboxylic acids byreducing the corresponding Weinreb amides or reduction of carboxylicacid derivatives, see (a) S. M. Weinreb et al. Tetrahedron Lett. 1981,22, 3815-3818; (b) M. Braun, Synthesis 1989, 856; and (c) D. A. Evans,J. Org. Chem. 1993, 58, 2446-2453.

Aminoaldehydes used in the synthesis of the compounds of the inventionmay be prepared by oxidation of corresponding amino alcohols orreduction of corresponding amino acids; see (a) J. Jurczak et al.,Synlett 1993, 241; and (b) S. G. Davis et al., Synlett 1995, 700.

Sulfur containing aldehydes used in the synthesis of compounds of theinvention may be made by conjugate addition of a thiol toα,β-unsaturated aldehydes or reaction of a thiol with a halosubstitutedaldehyde. See T. Cohen et al., J. Org. Chem. 1995, 60, 2022; Tetrahdron1994, 50, 12793-12810; J. Org. Chem. 1992, 57, 6; Phosphorus, Sulfur,and Silicon 1993, 74, 1; and Tetrahdron 1994, 50, 11569-11584.

Sulfoxides and sulfones are prepared from the corresponding sulfide byoxidation. See M. Hudlicky, Oxidations in Organic Chemistry, ACS, 1990;pp 250-264.

The acid chlorides used in Scheme 1 are either commercially available orprepared from commercially available or readily accessible carboxylicacids by the action of oxalyl chloride or thionyl chloride. See R. C.Larock, Comprehensive Organic Transformations, Wiley-VCH: 1989; pp963-964.

EXAMPLES

Chemical abbreviations used in the Examples are defined as follows:“DMPU” for 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone; “TBTU” forO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate;“BOP” for benzotriazol-1-yloxytris-dimethylamino)-phosphoniumhexafluorophosphate; “Bu₂BOTf” for dibutylboron triflate; “EDC” for1-[3-(dimethylamine)propyl]-3-ethylcarbodiimide hydrochloride; “HOBt”for 1-hydroxybenzotriazole; “TPAP” for tetrapropylammonium perruthenate;“NMO” for 4-methylmorpholine N-oxide; and “TEA” for triethylamine.

“HPLC” is an abbreviation used herein for high pressure liquidchromatography. Compounds of the present invention are generallypurified by HPLC using conditions known to one skilled in the art.However, unless otherwise indicated, the following conditions aregenerally applicable. Reverse-phase HPLC can be carried out using aVydac C-18 column with gradient elution from 10% to 100% buffer B inbuffer A (buffer A: water containing 0.1% trifluoroacetic acid, bufferB: 10% water, 90% acetonitrile containing 0.1% trifluoroacetic acid).Alternatively, reverse-phase HPLC can be carried out using a Vydac C-18column with gradient elution from 10% to 90% acetonitrile in water.

Example 1 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(R)-3-(3-cyclopentyl-1-oxopropyl)-4-(phenylmethyl)-2-oxazolidinone (2)

A dry round bottom flask was charged with of(R)-4-(phenylmethyl)-2-oxazilidinone (1, 17.7 g, 0.100 mol). Anhydroustetrahydrofuran (300 mL) was then added, and the solution was cooled to−78° C. A solution of butyllithium (42.0 mL, 0.105 mol, 2.50 M inhexane) was added to the reaction flask over a 10-min period. After afew minutes, 3-Cyclopentylpropionyl chloride (16.8 mL, 0.110 mol) wasadded. The resulting solution was stirred for 30 min at −78° C., thenallowed to warm to ambient temperature over a 30-min period. Excess3-cyclopentylpropionyl chloride was quenched by the addition of 60 mL ofsaturated aqueous ammonium chloride. The bulk of the tetrahydrofuran andhexane was removed on a rotary evaporator, and the slurry was extricatedwith two 80 mL portion of dichloromethane. The combined organic layerswere washed with 75 mL of 1 M sodium hydroxide and 75 mL of brine, driedover anhydrous magnesium sulfate, and filtered. The solvent was removedunder reduced preddure. The residue was trituated with hexane to provide16.5 g of desired product 2 as a white solid. ¹H NMR (300 MHz, CDCl₃) δ7.18-7.40 (5H, m), 4.67 (1H, m), 4.12-4.22 (2H, m), 3.30 (1H, dd,J=13.4, 3.1 Hz), 2.84-3.06 (2H, m), 2.76 (1H, dd, J=13.4, 9.6 Hz),1.42-1.96 (9H, m), 1.15 (2H, br, m).

3-(2(R)-cyclopentylmethyl-3(S)-hydroxyl-5-phenyl-1-oxopentyl)-4(R)-(phenylmethyl)-2-oxazolidinone(3)

To a solution of acyloxazolidinone 2 (1.57 g, 5.00 mmol) in 20 mL ofdichloromethane, cooled to −78° C. under nitrogen atmosphere,dibutylboron triflate (1.40 mL, 5.50 mmol) was added dropwise, followedby the addition of triethylamine. The mixture was warmed slowly to 0° C.and was stirred at 0° C. for an additional hour. The resultant borylenolate solution was then cooled to −78° C., and 3-phenylpropanal (0.80mL, 5.5 mmol) was added over a 5-min period time. The solution wasstirred for 1 h at −78° C., then for 1 h at 0° C. The reaction mixturewas quenched by the addition of 4 mL of a pH 7 aqueous phosphate bufferand 12 mL of methanol. To this cloudy solution was added 8 mL ofmethanol and 10 mL of 30% aqueous hydrogen peroxide at such a rate as tokeep the internal temperature below 10° C. After the solution wasstirred for one additional hour, the volatile material was removed in arotary evaporator. The resulting slurry was extracted with three 20 mLportions of diethyl ether. The combined organic layers was washed with20 mL of 5% aqueous sodium bicarbonate and 20 mL of brine, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. Purification by flash column chromatography (25% ethylacetate-hexane) provided 1.11 g (56%) of aldol 3 as a colorless oil. ¹HNMR (300 MHz, CDCl₃) δ 7.15-7.38 (m, 10H), 4.72 (m, 1H), 4.12-4.28 (m,3H), 3.85 (m, 1H), 3.34 (1H, dd, J=13.4, 3.1 Hz), 2.80-2.95 (1H, m),2.60-2.78 (2H, m), 1.95-2.05 (1H, m), 1.40-1.90 (10H, m), 1.10 (2H, m).

2(R)-cyclopentylmethyl-3 (S)-hydroxyl-5-phenylpentanoic acid (4)

Acyloxazolidinone 3 (226 mg, 0.500 mmol) was dissolved in 3 mL of THFand 1 mL of distilled water. The resulting solution was cooled to 0° C.To this solution was added 30% aqueous hydrogen peroxide (0.40 mL, 4.0mmol), followed by a solution of lithium hydroxide (19 mg, 0.80 mmol) in0.5 mL of distilled water. After the solution was stirred for 16 h,sodium sulfite (567 mg, 4.50 mmol) in 3 mL of distilled water was added.The bulk of tetrahydrofuran was removed under reduced pressure, and theresulting mixture (pH 12˜13) was extracted with three 20 mL portion ofmethylene chloride to remove the oxazolidinone auxiliary. The aqueouslayer was cooled in an ice bath and acidified to pH 1 with 6 M aqueoushydrochloric acid. The resulting cloudy solution was extracted with fiveportion of 30 mL ethyl acetate. The combined organic layers are driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure to yield 230 mg (81%) of the desired acid 4 as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 7.18-7.35 (5H, m), 3.87 (1H, m),2.81-2.87 (1H, m), 2.60-2.76 (1H, m); 2.54-2.60 (1H, m), 1.00-1.95 (m,13H).

3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(6)

A mixture of acid 4 (250 mg, 0.900 mmol) and3-amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-onep-toluenesulfonate salt (364 mg, 0.820 mmol) in 4 mL of methylenechloride was stirred at 0° C. 1-Hydroxy-benzotriazole hydrate (133 mg,0.980 mmol), 1-[3-(dimethylamine)propyl]-3-ethylcarbodiimidehydrochloride (314 mg, 1.64 mmol) and triethylamine (0.51 mL, 3.7 mmol)were added sequentially. After the mixture was stirred for 16 h, 30 mLof ethyl acetate was added. The organic layer was washed with 1 M HCl(15 mL), 5% NaHCO₃ (30 mL) and brine (30 mL), dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. Purificationby chromatotron (30% ethyl acetate-hexane) afforded two diastereomers Aand B. A: 120 mg (25%); ¹H NMR (300 MHz, CDCl₃) δ 7.20-7.70 (15H, m),5.54 (1H, d, J=8.0 Hz), 4.02 (1H, m), 3.48 (3H, s), 2.83-3.00 (1H, m),2.62-2.74 (1H, m), 2.40-2.48 (1H, m), 1.00-2.00 (13H, m); MS (ESI): 524(M+H), 546 (M+Na), 522 (M−H), 558 (M+Cl). B: 120 mg (25%); ¹H NMR (300MHz, CDCl₃) δ 7.60 (1H, d, J=6.9 Hz), 7.20-7.45 (14H, m), 5.56 (1H, d,J=8.4 Hz), 3.84 (1H, m), 3.48 (3H, s), 2.83-3.00 (1H, m), 2.62-2.74 (1H,m), 2.50-2.60 (1H, m), 1.00-1.95 (13H, m); MS (ESI): 524 (M+H), 546(M+Na), 522 (M−H).

Examples 2-135

The general procedure for Example 1 was followed using the correspondingacid chloride, aldehyde, and substituted benzodiazepine, azepane orbisbenzodiazepine. Starting materials were either commercially availableor prepared by methods known to one skilled in the art.

Example 23-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-5-5-phenylpentyl)amino-1-methyl-5-(4-fluoro-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 542 (M+H); 564 (M+Na), 540 (M−H). Chromatography Note b andNote c. Example 33-(2(R)-Benzyl-3(S)-hydroxyl-1-oxo-5-(phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 532 (M+H), 530 (M−H). Chromatography Note a. Example 43-(2(R)-Isopropyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 484 (M+H), 506 (M+Na), 482 (M−H). Chromatography Note u andNote v. Example 53-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4-(3,5-difluorophenoxy)butyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 562 (M+H), 596 (M+Cl). Chromatography Note a. Example 63-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-(3,5-difluorophenoxy)butyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 536 (M+H), 558 (M+Na), 534 (M−H), 570 (M+Cl). ChromatographyNote u and Note v. Example 73-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 560 (M+H), 582 (M+Na), 558 (M−H). Chromatography Note u andNote v. Example 8 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7-chloro-1-methyl-5-(4-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 552 (M+H), 574 (M+Na), 550 (M−H). Chromatography Note v.Example 93-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 464 (M+H), 462 (M+Cl). Chromatography Note a. Example 103-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 506 (M+H), 504 (M−H). Chromatography Note u and Note v.Example 11 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 492 (M+H), 514 (M+Na), 490 (M−H). Chromatography Note u andNote v. Example 123-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 534 (M+H), 532 (M−H). Chromatography Note v. Example 133-(2(R)-Benzyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 574 (M+H), 572 (M+Cl). Chromatography Note u and Note v.Example 143-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 566 (M+H), 588 (M+Na), 564 (M−H). Chromatography Note u andNote v. Example 153-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 540 (M+H), 562 (M+Na), 538 (M−H). Chromatography Note u andNote v. Example 163-(2(R)-Isopropyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 526 (M+H), 548 (M+Na), 524 (M−H). Chromatography Note v.Example 173-(2(R)-Methoxy-3(S)-hydroxyl-1-oxo-4-(4-trifluoromethylbenzyloxy)butyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 590 (M+H), 612 (M+Na), 588 (M+Cl). Chromatography Note u andNote v. Example 183-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-(2,4-difluorobenzyloxy)butyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 542 (M+H), 564 (M+Na), 540 (M−H). Chromatography Note u andNote v. Example 203-(2(R)-Vinyl-3(S)-hydroxyl-1-oxo-4-benzyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 536 (M+H), 558 (M+Na), 534 (M−H). Chromatography Note a.Example 213-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 498 (M+H), 520 (M+Na), 496 (M+Cl). Chromatography Note u andNote v. Example 233-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 498 (M+H). Example 243-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-3-cyclopropylpropyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 434 (M+H). Example 25a3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 450 (M+H). Example 25b3-(R)-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 450 (M+H). Example 25c3-(S)-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 450 (M+H). Example 263-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-nonyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 478 (M+H). Example 273-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 436 (M+H). Example 283-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenylbutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 484 (M+H). Example 293-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 442 (M+H). Example 303-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-6-phenylhexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 470 (M+H). Example 313-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-butyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS(ESI): 408 (M+H). Example 323-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-octyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 464 (M+H). Example 33 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 408 (M+H). Example 34 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3-phenylpropyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 428 (M+H). Example 353-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-5,5-dimethyl-hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 422 (M+H). Example 363-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 394 (M+H). Example 373-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3-(4-propoxyphenyl)propyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 486 (M+H). Example 382-(R)-cyclopropylmethyl-3-(S)-hydroxylheptanoic acid(2-oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl)amide. MS (ESI): 493 (M+H),491 (M−H), 527 (M+Cl). Example 392(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3-(S)-hydroxypentanoicacid (2-oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl)amide. MS (ESI): 577(M+H), 575 (M−H), 599 (M+Na). Example 404-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxybutanoic acid(2-oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl)amide. MS (ESI): 519 (M+H),541 (M+Na), 517 (M−H). Example 412-(R)-cyclopropylmethyl-3-(S)-hydroxyheptanioc acid(1-(5-bromo-3-pyridinyl)methyl-2-oxo-azapan-3-(S)-yl) amide. MS (ESI):480 (M(⁷⁹Br)+H), 482 (M(⁸¹Br+H), 478 (M(⁷⁹Br)+H), 480 (M(⁸¹Br)—H).Example 423-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 466 (M+H), 488 (M+Na), 464 (M−H). Chromatography Note b andNote c. Example 433-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(azapan-1-yl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 469 (M+H), 491 (M+Na), 467 (M−H). Chromatography Note b andNote c. Example 443-(2-(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 533 (M+H), 555 (M+Na), 531 (M−H). Chromatography Note b andNote c.

The 3-(3,5-difluorophenyl)propanal used in the aldol reaction wasprepared from trans-3,5-difluorocinnamic acid by: (1) hydrogenation to3-(3,5-difluorophenyl)propionic acid (L. Kruse et al J. Med. Chem. 1987,30, 486-494); (2) formation of Weinreb amide (M. Braun Synthesis 1989,856); and (3) reduction to aldehyde (D. A. Evans J. Org. Chem. 1993, 58,2446-2453).

Example 453-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(4-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 482 (M+H), 504 (M+Na), 480 (M−H). Chromatography Note i andNote k. Example 463-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-methoxyphenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 466 (M+H), 488 (M+Na), 464 (M−H). Chromatography Note b andNote c. Example 473-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-methoxyphenyl)-1-methyl-2,3-dihydro-1H-1,4-benxodiazepin-2-one.MS (ESI): 479 (M+H), 500 (M+Na), 476 (M−H). Chromatography Note m.Example 483-(S)-(4-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxobutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 474 (M+H), 496 (M+Na), 472 (M−H). Example 493-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxohept-6-enyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 446 (M+H), 468 (M+Na), 444 (M−H). Example 503-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxohept-6-enyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 514 (M+H). Chromatography Note i. Example 513-(S)-(2-(R)-cyclopropylmethyl-5-(3,5-dimethylisoxazol-4-yl)-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 515 (M+H), 537 (M+Na), 513 (M−H).

The 3-(3,5-dimethyl-4-isoxazole)propanal used in the aldol reaction wasprepared from: (1) methyl 3-(3,5-dimethyl-4-isoxazole)propionate (M. C.Marcotullio J. Org. Chem 1994, 59, 2884); (2) DIBAL-H reduction toalcohol (N. M. Yoon et al J. Org. Chem. 1985, 50, 2443-2450); and (3)TPAP/NMO oxidation to aldehyde (S. V. Ley et al Synthesis 1994, 639).

Example 523-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 482 (M+H), 504 (M+Na), 480 (M−H). Chromatography Note n andNote o. Example 533-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-(pyridin-2-yl)-2,3-dihydro-1H-1,4benzodiazepin-2-one. MS (ESI): 449 (M+H), 471 (M+Na), 447 (M−H).Chromatography Note b and Note c. Example 543-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-S-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 466 (M+H), 500 (M+Cl). Chromatography Note h. Example 553-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-S-(4-trifouoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 516 (M+H), 514 (M−H), 550 (M+Cl). Chromatography Note i.

The 3-cycloproyl propionic acid, which was converted to 3-cycloproylpropionyl chloride used in the aldol reaction, was prepared accordingto: A. Donetti J. Med. Chem. 1972, 15, (6), 590-592.

Example 563-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 489 (M+H), 511 (M+Na), 487 (M−H). Chromatography Note b andNote c. Example 573-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 518 (M+H), 540 (M+Na), 516 (M−H). Chromatography Note b andNote c. Example 583-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxo-5-(thiophen-2-yl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 502 (M+H), 524 (M+Na), 500 (M−H). Example 593-(S)-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 486 (M+H), 508 (M+Na), 484 (M−H). Example 603-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 506 (M+H), 528 (M+Na), 504 (M−H). Chromatography Note h.Example 613-(S)-(2-(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3-(S)-hydroxy-1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 532 (M+H), 554 (M+Na), 530 (M−H). Example 623-(S)-(3-(S)-hydroxyl-2-(R)-(thiophen-2-yl)methyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 448 (M+H), 470 (M+Na), 446 (M−H). Example 633-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-7-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 490 (M+H), 512 (M+Na), 488 (M−H). Example 643-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-7-methoxy-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 478 (M+H), 500 (M+Na), 476 (M−H). Chromatography Note 1.Example 653-(S)-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 462 (M+H), 484 (M+Na).

The 3-cyclobutyl propionic acid, which was converted to 3-cyclobutylpropionyl chloride used in the aldol reaction, was prepared accordingto: A. Donetti J. Med. Chem. 1972, 15, (6), 590-592.

Example 663-(S)-(2-(R)-(3,5-difluorobenzyl)-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiaxepin-2-one.MS (ESI): 520 (M+H), 518 (M−H). Example 673-(S)-(2-(R)-(furan-2-yl)methyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 474 (M+H), 472 (M−H). Example 683-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-S-(pyridin-2-yl)-2,3-dihydro-1H-benzodiazepin-2-one.MS (ESI): 514 (M+H), 536 (M+Na), 512 (M−H). Chromatography Note h.Example 693-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 497 (M+H), 519 (M+Na), 495 (M−H). Chromatography Note b andNote c. Example 703-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 468 (M+H), 502 (M+Cl). Chromatography Note h. Example 713-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 421 (M+H), 443 (M+Na), 419 (M−H). Chromatography Note b andNote c. Example 723-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 554 (M+H), 576 (M+Na), 552 (M−H). Chromatography Note i.Example 733-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 542 (M+H), 564 (M+Na), 540 (M−H). Chromatography Note i.Example 743-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxooctyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 530 (M+H), 552 (M+Na), 528 (M−H). Chromatography Note i.Example 753-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxononyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 544 (M+H), 566 (M+Na), 542 (M−H). Chromatography Note i.Example 763-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl(pyridin-2-yl))-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 517 (M+H), 539 (M+Na), 515 (M−H). Chromatography Note i.Example 773-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(40trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 530 (M+H), 552 (M+Na), 528 (M−H). Chromatography Note i.Example 783-(2-(R)-cyclopentylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-S-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 544 (M+H), 542 (M−H), 578 (M+Cl). Chromatography Note i.Example 793-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 463 (M+H). Chromatography Note cc. Example 803-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-S-(4-methyl-2-pyridyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 463 (M+H). Chromatography Note dd. Example 813-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxobutyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 474 (M+H). Chromatography Note i. Example 823-(S)-(2-(R)-(3-butenyl)-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 448 (M+H). Example 833-(S)-(2-(R)-(3-methylbutyl)₃-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 464 (M+H). Example 843-(S)-(2-(R)-ethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 422 (M+H). Example 853-(S)-(2-(R)-propyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepin-2-one.MS (ESI): 436 (M+H). Example 863-(S)-(2-(R)-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 450 (M+H). Example 873-(4-(S)-amino-3-(R)-hydroxyl-2-(R)-methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 523 (M+H), 521 (M−H). Chromatography Note x. Example 883-(4-(S)-(tert-butoxycarbonylamino-3-(R)-hydroxyl-2-(R)-methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 645 (M+H), 621 (M−H). Chromatography Note a and Note u.Example 893-(3-(tert-butoxycarbonylpyrrolidin-2-(R)-yl)-3-(R)-hydroxyl-2-(R)-methyl-1-oxopropyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 523 (M+H), 521 (M−H). Chromatography Note u and Note v.Example 903-(3-(R)-hydroxyl-2-(R)-methyl-1-oxo-3-(pyrrolidin-2-(R)-yl)propyl)-amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 473 (M+H), 471 (M−H). Chromatography Note y and Note z.Example 913-(4-benzyloxy-3-(R)-hydroxyl-2-(R)-iso-propyl-1-oxobutyl-amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 534 (M+H), 556 (M+Na), 532 (M−H). Chromatography Note u andNote v. Example 922-(4-(S)-amino-3-(S)-hydroxyl-2-(S)-methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2-flourophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 523 (M+H), 521 (M−H). Chromatography Note w. Example 932-(4-(S)-(tert-butoxycarbonylamino-3-(S)hydroxyl-2-(S)-methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 645 (M+Na), 621 (M−H). Chromatography Note a and Note v.Example 943-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(thiazol-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 455 (M+H), 477 (M+Na), 453 (M−H). Chromatography Note b andNote c.

The benzodiazepine was made from 2-aminophenyl-2′thiazolylketone (see A.Furstner et al., Tetrahedron 1995, 51 (3), 773-786) following thesynthetic sequence from: R. G. Sherrill et al., J. Org. Chem. 1995, 60,734.

Example 953-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-cyclopropylmethyl-5-(thiazol-2-yl)-2,3-dihydro-1H-1,4benzodiazepin-2-one.MS (ESI): 495 (M+H), 517 (M+Na), 493 (M−H). Chromatography Note c.

The benzodiazepine was made from 2-aminophenyl-2′thiazolylketone (see A.Furstner et al., Tetrahedron 1995, 51 (3), 773-786) following thesynthetic sequence from: R. G. Sherrill et al., J. Org. Chem. 1995, 60,734.

Example 963-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-cyclopropylmethyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 556 (M+H), 578 (M+Na), 554 (M−H). Chromatography Note j andNote p. Example 973-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 592 (M+H), 614 (M+Na), 590 (M−H). Chromatography Note b andNote c. Example 983-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-phenoxybenzyl)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 684 (M+H), 706 (M+Na), 682 (M−H). Chromatography Note q andNote r. Example 993-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-pyridinylmethyl)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 593 (M+H), 615 (M+Na), 519 (M−H). Chromatography Note q andNote r. Example 1003-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 516 (M+H), 538 (M+Na), 514 (M−H). Chromatography Note i.

The syn-aldol was made according to Scheme 1, except that(S)-4-(phenylmethyl)-2-oxazolidinone was used instead of the (R)-isomershown in Scheme 1.

Example 1013-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 516 (M+H), 538 (M+Na), 514 (M−H). Chromatography Note k.

The syn-aldol was made according to Scheme 1, except that(S)-4-(phenylmethyl)-2-oxazolidinone was used instead of the (R)-isomershown in Scheme 1.

Example 1023-(2-(R)-cyclopropylmethyl-3-(R)-hydroxyl-1-oxoheptyl)amino-1-methyl-S-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 516 (M+H), 538 (M+Na), 514 (M−H). Chromatography Note i.

The anti-aldols were made by the method described in: A. K. Ghosh, J.Am. Chem. Soc. 1996, 118, 2527-2528. The carboxylic acid shown wascoupled with the corresponding benzodiazepine following a procedureanalogous to the procedure of the last step in Example 1.

Example 1033-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-S-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 516 (M+H), 538 (M+Na), 514 (M−H). Chromatography Note i.

Followed the synthetic sequence of Example 102, except the oppositeenantiomer of the chiral auxiliary was used.

Example 1043-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 516 (M+H), 514 (M−H). Chromatography Note k.

Followed the synthetic sequence of Example 102, except the oppositeenantiomer of the chiral auxiliary was used.

Example 1053-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-3-(S)-methyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 530 (M+H), 552 (M+Na), 528 (M−H). Chromatography Note i.

Addition of a methyl group to Example 135 was performed with anorganocerium reagent generated from methylmagnesium bromide and ceriumtrichloride according to: T. Imamoto et al (a) J. Org. Chem. 1984, 49,3904-3912, and (b) J. Am. Chem. Soc. 1989, 111, 4392-4398.

Example 1063-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-phenoxybenzyl)-5-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 554 (M+H). Chromatography Note aa and Note bb. Example 1073-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 462 (M+H). Chromatography Note b and Note c. Example 1083-(3-(S)-acetoxy-2-(R)-iso-butyl-1-oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 510 (M+H), 532 (M+Na), 508 (M−H). Chromatography Note h.Example 1093-(S)-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-methoxy-1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 502 (M+H), 524 (M+Na).

Methylation of the corresponding aldol was carried out according to: (a)D. A. Evans et al., Tetrahedron Lett. 1994, 35 (39), 7171-7172; (b) G.R. Pettit, Synthesis 1996, 719-725. The carboxylic acid shown was thencoupled with the corresponding benzodiazepine following a procedureanalogous to the procedure of the last step in Example 1.

Example 113 1-(1-hydroxypentyl)cyclohexanecarboxylicacid(5-(4-fluorophenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)amide.MS (ESI): 480 (M+H), 502 (M+Na), 478 (M−H). Chromatography Note t andNote h.

The corresponding aldol was made according to (a) A. S. Kende et al.,Tetrahedron Lett. 1989, 30 (43), 5821-5824; (b) H. Mulzer et al.,Tetrahedron Lett. 1995, 36 (42), 7643-7646. The carboxylic acid shownwas coupled with benzodiazepine following a procedure analogous to theprocedure of the last step in Example 1.

Example 1143-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one.MS (ESI): 421 (M+H), 443 (M+Na), 419 (M−H). Chromatography Note s.Example 1153-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxooctyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one.MS (ESI): 435 (M+H), 457 (M+Na), 433 (M−H). Chromatography Note s.Example 1163-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxononyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one.MS (ESI): 449 (M+H), 471 (M+Na), 447 (M−H). Chromatography Note s.Example 1173-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3-(S)-hydroxyl-1-oxopentyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one.MS (ESI): 459 (M+H), 481 (M+Na), 457 (M−H). Chromatography Note s.Example 118 2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-heptanoic acid(2-oxo-1-(3-phenylamino-benzyl)azapan-3-(S)-yl) amide. MS (ESI): 492(M+H), 514 (M+Na), 490 (M−H).

Step 1: [2-Oxo-1-(3-phenylamino-benzyl)-azepan-3-yl]-carbamic acidtert-butyl ester: In a 100 ml round bottomed flask Binap,(S)-(−)2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl, (0.210 g, 0.3375mmol) dissolved in 15 mL toluene was stirred at 80° for 1 minute. To theflask cooled to room temperature under inert atmosphere Pd(OAC)₂ (0.050g, 0.225 mmol) was added and the solution was stirred at roomtemperature for 2 minutes. To the reaction mixture[1-(3-Iodo-benzyl)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester(1.0 g, 2.25 mmol) dissolved in 15 mL toluene, aniline (1.047 g, 11.25mmol) and Sodium tert-butoxide (0.259 g, 2.70 mmol) were added and thesolution was stirred at 80° C. for 18 h. The reaction was cooled to roomtemperature, diluted with 200 mL of water, and extracted twice with 100mL of ethyl acetate. The organic layer was dried with anhydrous sodiumsulfate, filtered and concentrated to an oil. The oil was purified onflash silica gel column using 10-30% ethyl acetate in hexanes as eluentto yield 0.562 g (61%). MS (ESI) M+H=432.5

Step 2: 3-Amino-1-(3-phenylamino-benzyl)-azepan-2-one, trifluoroaceticacid salt: In a 25 mL round bottomed flask the ester from Step 1 above(0.025 g, 0.06 mmol) was dissolved in 10 mL of 50% TFA/CH₂Cl₂ and wasstirred at room temperature for 1 h. The solvent was concentrated to anoil and dried under high vacuum to yield 0.025 g (100%). MS (ESI)M+H=310.4

Step 3: 2-Cyclopropylmethyl-3-hydroxy-heptanoic acid[2-oxo-1-(3-phenylamino-benzyl)-azepan-3-yl]-amide: In a 25 mL roundbottomed flask 2-Cyclopropylmethyl-3-hydroxy-heptanoic acid (0.0125 g,0.061 mmol) was dissolved in 1 mL DMF. To the reaction mixture HATU,O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, (0.029 g, 0.0734 mmol) and N-Methyl morpholine(0.018 g, 0.018 mmol) were added and the reaction solution was stirredat room temperature for 10 minutes. To the reaction mixture the compoundfrom Step 2 above (0.025 g, 0.06 mmol) dissolved in 1 mL of DMF wasadded and the reaction solution was stirred at room temperature for 18h. The solution was diluted with 50 mL of water and extracted twice with20 mL of ethyl acetate. The combined organic layers were dried withanhydrous Sodium sulfate, filtered, and concentrated to an oil. The oilwas purified on a flash silica gel column using 20-40% ethyl acetate inhexanes as eluent to yield 6.0 mg (20%). MS (ESI) M+H=492.6

Example 1193-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-cyclopentyl-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 440 (M+H). Chromatography Note a.

Synthesis of 2-aminophenyl cyclopentylmethanone: To a solution ofanthranilonitrile (15.0 g) in diethyl ether (600 mL) was added asolution of 2.0 M cyclopentylmagnesium bromide in diethyl ether (159 mL)at 0° C. under nitrogen. The mixture was stirred at room temperatureovernight (20 hours). 500 ml of 5 N HCl in H₂O was added very slowly at0° C. The mixture was stirred at room temperature for 1 hour. Theaqueous layer was neutralized with 50% NaOH/H₂O to pH=12. 2×500 mL ofethyl acetate was used to extract the aqueous layer. The combinedorganic layers were dried over Na₂SO₄. The solvent was removed to givethe crude product 22.5 g (93.6% yield). H¹NMR(CDCl₃): δ6.62-7.82 (m,4H), 3.64-3.78 (m, 1H), 1.50-1.96 (m, 8H).

The 2-aminophenyl cyclopentylmethanone was converted to benzodiazepinefollowing: R. G. Sherrill et al J. Org. Chem. 1995, 60, 734.

Example 1203-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-benzyl-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 462 (M+H), 460 (M−H). Chromatography Note b and Note c.

The benzodiazepine was made from 1-(2-aminophenyl)-2-phenylethanone (seeM. W. Partridge et al., J. Chem. Soc. 1964, 3673) following thesynthetic sequence from: R. G. Sherrill, J. Org. Chem. 1995, 60, 734.

Example 1213-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-benzyl-1-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 504 (M+H), 502 (M−H). Chromatography Note b and Note c.Example 1223-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-cycloheptyl-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 468 (M+H), 466 (M−H). Chromatography Note b and Note c.Example 1233-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-cycloheptyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 544 (M+H), 542 (M−H). Chromatography Note a. Example 1243-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-butyl-5-cycloheptyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 510 (M+H), 508 (M−H). Chromatography Note b and Note c.Example 1253-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-pyridinylmethyl)-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 593 (M+H), 615 (M+Na), 591 (M−H). Chromatography Note a.Example 1263-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-pyridinylmethyl)-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 543 (M+H), 541 (M−H). Chromatography Note d and Note e.Example 1273-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-(3-pyridinylmethyl)-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 565 (M+H), 563 (M−H). Chromatography Note f and Note g.Example 1283-(2-[(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(N,N-dibutylamino)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 499 (M+H). Chromatography Note a. Example 1293-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-n-butyl-5-t-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 470 (M+H). Chromatography Note b and Note c.

The benzodiazepine can be made from 2-amino-pivalophenone (A. Furstneret al., J. Org. Chem. 1994, 59 (18), 5215-5229; M.-C. Bettembourg etal., Bull. Soc. Chim. Fr. 1963, 2449-2451) following the syntheticsequence from: R. G. Sherrill et al., J. Org. Chem. 1995, 60, 734.

Example 1303-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-oxo-3,3-dimethylbutyl)-5-n-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 512 (M+H). Chromatography Note b. Example 1313-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-t-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 504 (M+H). Chromatography Note a.

The benzodiazepine can be made from 2-amino-pivalophenone (A. Furstneret al., J. Org. Chem. 1994, 59 (18), 5215-5229; M.-C. Bettembourg etal., Bull. Soc. Chim. Fr. 1963, 2449-2451) following the syntheticsequence from: R. G. Sherrill et al., J. Org. Chem. 1995, 60, 734.

Example 1323-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-picolyl)-5-n-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 505 (M+H). Chromatography Note b and Note c. Example 1333-(2-(R)-Isobutyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-homopiperidino-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 471 (M+H). Chromatography Note b and Note c. Example 1353-(2-(R)-cyclopropylmethyl-1,3-dioxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 514 (M+H), 536 (M+Na), 512 (M−H). Chromatography Note i.

Example 55 was oxidized to the dicarbonyl compound by TPAP/NMO, see S.V. Ley et al., Synthesis 1994, 639.

Example 136 1-pentyrylcyclohexanecarboxylic acid(5-(4-fluorophenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)amide.MS (ESI): 478 (M+H), 500 (M+Na), 476 (M−H). Chromatography Note h.Example 137(2R,3S)—N-[1-butyl-5-(methylethyl)-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]-2-(cyclopropylmethyl)-3-hydroxyheptanamide.MS (ESI): 456 (M+H). Example 138(2R,3S)-2-(cyclopropylmethyl)-3-hydroxy-N-[5-(methylethyl)-2-oxo-1-benzyl(3H-benzo[f]1,4-diazepin-3-yl)]heptanamide.MS (ESI): 490 (M+H). Example 139(2R,3S)-2-(cyclopropylmethyl)-3-hydroxy-N-{5-methyl-1-[(3-{[(4-methylphenyl)sulfonyl]amino}phenyl)-methyl]-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)}heptanamide.MS (ESI): 631 (M+H). Example 1403-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-t-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 428 (M+H). Example 141(2R,3S)-2-(cyclopropylmethyl)-3-hydroxy-N-{1-[(3-{([(4-methylphenyl)sulfonyl]amino}phenyl)methyl]-2-oxo(3H,4H,5H-benzo[f]1,4-diazaperhydroepin-3-yl)}heptanamide.MS (ESI): 570 (M+H). Example 1423-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-piperizinyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 456 (M+H). Example 1437-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(2-diethylaminoethyl)-6,7-dihydro-5H-dibenzoazepin-6-one.MS (ESI): 506 (M+H). Example 1447-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(3-hydroxypropyl)-6,7-dihydro-5H-dibenzoazepin-6-one.MS (ESI): 465 (M+H). Example 1453-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(benzyl-5-(2,2-dimethylpropyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 518 (M+H). Example 1463-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-n-butyl-5-n-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 506 (M+H). Example 1473-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-n-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 504 (M+H). Example 1483-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 503 (M+H). Example 1493-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(2,2-dimethylpropyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 442 (M+H). Example 1507-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-n-butyl-6,7-dihydro-5H-dibenzoazepin-6-one.MS (ESI): 442 (M+H). Example 1513-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-ethylbutyl)-S-n-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 498 (M+H). Example 1523-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-pyrrolidin-1-yl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 441 (M+H). Example 1537-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-benzyl-6,7-dihydro-5H-dibenzoazepin-6-one.MS (ESI): 497 (M+H). Example 1543-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-hydroxypropyl)-5-t-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 472 (M+H). Example 1553-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-ethoxy-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 416 (M+H). Example 1563-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-butyl-5-(2,2-dimethylpropyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 484 (M+H). Example 1573-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-pyridinylmethylN-oxide)-5-(4-trifluoromethyl)phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 609 (M+H). Example 1583-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-pyridinylmethylN-oxide)-5-(4-trifluoromethyl)phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 609 (M+H). Example 1593-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-(3-pyridinylmethyl)-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 497 (M+H). Example 1603-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-(diethylamino)ethyl)-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 601 (M+H). Example 1613-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-(3-pyridinylmethylN-oxide)-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 513(M+H).

Example 159 (28 mg, 0.056 mmol) and m-CPBA (12.6 mg, 0.056 mmol) weredissolved in methylene chloride (1 mL) and stirred at room temperaturefor 20 h. The reaction mixture was concentrated and purified on silicagel (3% methanol/methylene chloride) to afford Example 161 (28 mg, 100%)as a white solid. MS m/z 513.5 (M+H).

Example 162(2R,3S)—N-(8-bromo-1,5-dimethyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(cyclopropylmethyl)-3-hydroxyheptanamide.

Step A: Preparation of 1-(2-amino-4-bromophenyl)ethanone (162a)

Under an argon atmosphere a solution of 3-bromoaniline (31.3 g, 181.8mmol) and acetonitrile (75 g, 1.818 mol) in anhydrous toluene (120 ml)was added dropwise to boron trichloride (23.4 g, 200 mmol) in (200 ml)hexanes under cooling in an ice bath and stirring over 2.5 hours. Afterthe addition was completed, aluminum chloride (26.6 g, 200 mmol) wasadded portion wise over 30 minutes. The mixture was allowed to warm toambient temperature and then heated at reflux for 16 hours withstirring. A 3N HCl solution (100 ml) was added dropwise to the reactionmixture under stirring at 10° C. After the addition was complete, themixture was heated at reflux for 3.5 hours. The reaction mixture wasthen cooled to room temperature, and the layers separated. The aqueouslayer was extracted with chloroform (3×250 ml). Organic layers werecombined, dried over magnesium sulfate, filtered, and the filtrateconcentrated to give the title compound 162a (9.58 g, 25%). ¹H NMR(CDCl₃, 300 MHz): δ 7.54 (d, 1H, J=8.8 Hz), 6.83 (d, 1H, J=1.9 Hz), 6.75(dd, 1H, J=8.4, 1.8 Hz), 2.54 (s, 3H) ppm.

Step B: Preparation of benzyl8-bromo-5-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-ylcarbamate(162b)

Under an argon atmosphere1H-1,2,3-benzotriazol-1-yl{[(benzyloxy)carbonyl]amino}acetic acid (6.71g, 20.6 mmol) was suspended in anhydrous methylene chloride (92 ml) andcooled to 0° C. in an ice bath. Oxalyl chloride (2.61 g, 20.6 mmol) wasadded dropwise to the suspension, followed by N,N-dimethylformamide (38ml) added dropwise. After the addition the reaction was stirred at 0° C.in an ice bath for 30 minutes, until no more gas evolved. Then1-(2-amino-4-bromophenyl)ethanone (4.0 g, 18.7 mmol) and4-methylmorpholine (2.84 g, 28.0 mmol) were added dropwise in anhydrousmethylene chloride (60 ml) under stirring in an ice bath. The reactionmixture was then allowed to warm to room temperature and stirred overnight. Reaction was quenched with water (200 ml), then extracted withethyl acetate (3×250 ml). The organic layers were combined, dried overmagnesium sulfate, filtered, and the filtrate was concentrated to give aresidue. This residue was dissolved in tetrahydrofuran (120 ml) andmethyl alcohol (35 ml) and then ammonia gas was bubbled through for 2.5hours. The reaction was then concentrated to a very viscous light brownoil. The oil was dissolved in acetic acid (120 ml) and ammonium acetate(4.3 g, 56.1 mmol) was added in one portion and stirred for 12 hours.The reaction was diluted with water (100 ml) and then basified to pH=10with 25% sodium hydroxide under stirring in an ice bath. The aqueoussolution was then extracted with ethyl acetate (3×500 ml) and theorganic layers combined, dried over magnesium sulfate, filtered and thefiltrate concentrated to give a residue. The residue was purified tosilica gel column chromatography eluting with 40% ethyl acetate inhexanes to give the title compound 162b (4 g, 53%). ¹H NMR (CDCl₃, 300MHz): δ9.90 (s-br, 1H), 7.42-7.31 (m, 6H), 7.12 (d, 1H, 1.5 Hz),7.06-7.03 (m, 1H), 5.18-5.08 (m, 3H), 2.50 (s, 3H) ppm.

Step C: Preparation of benzyl8-bromo-1,5-dimethyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-ylcarbamate(162c)

162b (2.0 g, 4.98 mmol) was dissolved in anhydrous N,N-dimethylformamide(10 ml), to this was added potassium carbonate (1.72 g, 12.44 mmol) andiodomethane (0.847 g, 5.97 mmol) and the reaction was sealed in apressure flask and stirred for 12 hours at room temperature. Thereaction was diluted with water and ethyl acetate (20/70 ml). Theaqueous solution was then extracted with ethyl acetate (3×20 ml). Theorganic layers combined, washed with water (1×100 ml), dried overmagnesium sulfate, filtered and the filtrate concentrated to give thetitle compound 162c (1.58 g, 77.5%). ¹H NMR (CDCl₃, 300 MHz): δ7.43-7.28 (m, 7H), 6.68 (d, 1H, J=8.1 Hz), 5.15-5.05 (m, 3H), 3.38 (s,3H), 2.45 (d, 3H, 1.5 Hz) ppm.

Step D: Preparation of3-amino-8-bromo-1,5-dimethyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one(162d)

162c (0.831 g, 2.00 mmol) was dissolved in anhydrous anisole (16 ml) andthen methane sulfonic acid (3.84 g, 40 mmol) was added in one portion,and then the reaction was heated to 40° C. for 30 minutes with stirring.The reaction was cooled to 0° C. in an ice bath then basified to pH=10with concentrated ammonium hydroxide. The aqueous solution was thenextracted with chloroform (3×50 ml) and the organic layers combined,dried over magnesium sulfate, filtered and the filtrate concentrated togive a residue. The residue was purified to silica gel columnchromatography eluting with 10% methyl alcohol in chloroform to give thetitle compound 162d (0.463 g, 82%). ¹H NMR (CDCl₃, 300 MHz): δ 7.32-7.23(m, 3H), 4.12 (d, 1H, J=1.1 Hz), 3.27 (s, 3H), 2.30 (d, 3H, J=1.5 Hz)ppm.

Step E: Preparation of(2R,3S)—N-(8-bromo-1,5-dimethyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2-(cyclopropylmethyl)-3-hydroxyheptanamide(Example 162)

Under an argon atmosphere(2S,3R)-2-(cyclopropylmethyl)-3-hydroxyheptanoic acid (0.75 g, 3.74mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate were dissolved in anhydrous N,N-dimethylformamide (3ml) and stirred for 10 minutes. Then 1d (0.862 g, 3.06 mmol) andN,N-diisopropylethylamine (0.809 g, 6.24 mmol) in N,N-dimethylformamide(3 ml) were added and reaction was stirred at room temperature underargon for 12 hours. Reaction was quenched with water (20 ml), thenextracted with ethyl acetate (3×25 ml). The organic layers werecombined, dried over magnesium sulfate, filtered, and the filtrate wasconcentrated to give a residue. The residue was purified by silica gelcolumn chromatography eluting with 50% ethyl acetate in hexanes to givethe title compound Example 162 (1.31 g, 92%). ¹H NMR (CDCl₃, 300 MHz): δ7.46-7.40 (m, 3H), 5.36 (t, 1H, J=5.7 Hz), 3.94-3.81 (m, 1H), 3.41 (s,3H), 2.46-2.41 (m, 3H), 1.86-1.81 (m, 1H), 1.62-1.21 (m, 8H), 0.90 (t,2H, J=6.8 Hz), 0.80-0.773 (m, 1H), 0.494-0.400 (m, 1H), 0.116-0.001(m,3H) ppm.

Example 1636-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1,4-dibenzyl-hexahydro-5H-1,4-diazepin-5-one

N-Cbz-Dehydroalanine methyl ester (163a) (4.70 g, 0.02 mol) and1,4-dibenzylethylenediamine (163b) (24.00 g, 0.1 mol) were stirred for48 h at ambient temperature. The reaction mixture was subjected to flashcolumn chromatography on silica gel, using 5% methanol/methylenechloride, to give 163c (3.84 g, 40%) as a colorless oil. MS m/z 476.2(MH⁺).

To a solution of 163c (1.7 g, 3.6 mmol) in dry toluene (35 mL) was addedNaOCH₃ (1.94 g, 9.0 mmol, 25% in methanol). The reaction mixture wasrefluxed for 2 h, and then cooled to room temperature. The reactionmixture was diluted with ethyl acetate (50 mL), washed with water,brine, and dried (MgSO₄). After evaporation of the solvent, the residuewas purified on silica gel (2% methanol/methylene chloride) to afford163d (342 mg, 26%) as a colorless oil. MS m/z 368.5 (M+H).

163d (342 mg, 0.93 mmol) was dissolved in HBr/HOAc (5 mL, 30%) andstirred for 20 h at ambient temperature. The reaction mixture was thendiluted with ether (50 mL). The precipitate was filtered under nitrogenatmosphere, thoroughly washed with ether, and dried under high vacuumovernight to give a white solid 163e (340 mg, 100%). MS m/z 391.2 (M+H),310.2 (M+H−HBr).

163e (78 mg, 0.20 mmol), 163f (40 mg, 0.20 mmol), and HATU (91 mg, 0.24mmol) were dissolved in DMF (1 mL), diisopropylethylamine (0.12 mL, 0.70mmol) was added. After being stirred for 24 h at ambient temperature,the reaction mixture was diluted with ethyl acetate, washed with waterand brine, dried (Na₂SO₄). After evaporation of the solvent, the residuewas purified on silica gel (50% ethyl acetate/hexane) to afford Example163 (28 mg, 29%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ: −0.05-0.1(m, 2H), 0.3-0.5 (m, 2H), 0.5-0.7 (m, 1H), 0.89 (t, J=6.6 Hz, 3H),1.22-1.55 (m, 7H), 1.6-1.8 (m, 1H), 1.9-2.1 (m, 1H), 2.25-2.40 (m, 2H),2.65-2.80 (m, 1H), 3.08-3.21 (m, 2H), 3.45-3.85 (m, 4H), 4.55-4.70 (m,2H), 4.85-5.0 (m, 1H), 7.19 (d, J=1.8 Hz, 1H), 7.18-7.38 (m, 10H); MSm/z 492.6 (M+H).

Example 1646-(2-(R)-cyclopropylmethyl-3-(S)-hydroxy-1-oxoheptyl)amino-4-benzyl-1-[(4-chlorophenyl)sulfonyl]-hexahydro-5H-1,4-diazepin-5-one

To a solution of Example 163 (85 mg, 0.17 mmol) in THF (1 mL) and CH₃OH(1 mL) was added H₂O (0.5 mL), hydrochloric acid (conc. 0.1 mL), and 10%Pd/C (20 mg). The reaction flask was evacuated and then filled with H₂.This process was repeated three times, and the reaction mixture wasstirred under hydrogen atmosphere for 24 h at room temperature. Thereaction mixture was made basic with saturated Na₂CO₃, filtered througha pad of celite, and washed with ethyl acetate (100 mL). The filtratewas evaporated to give 164a (70 mg, 103%) as a colorless oil. MS m/z402.4 (M+H).

To a solution of 164a (68 mg, 0.17 mmol) in pyridine (1 mL) was addedp-chlorobenzenesulfonyl chloride (43 mg, 0.2 mmol), and the reactionmixture was stirred overnight at room temperature. Pyridine was removedvia rotovap. The residue was dissolved in ethyl acetate (20 mL), washedwith water, 1 N HCl, Na₂CO₃ (sat'd), brine, and dried (Na₂SO₄). Afterevaporation of the solvent, the residue was purified on silica gel (2%methanol/methylene chloride) to afford Example 164 (94 mg, 96%) as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ: −0.1-0.15 (m, 2H), 0.3-0.45 (m,2H), 0.5-0.65 (m, 1H), 0.78-0.89 (m, 3H), 1.15-1.52 (m, 7H), 1.55-1.70(m, 1H), 2.25-2.35 (m, 1H), 2.40-2.55 (m, 1H), 2.56-2.68 (m, 1H),3.15-3.28 (m, 1H), 3.32-3.48 (m, 1H), 3.50-3.85 (m, 3H), 4.02-4.18 (m,1H), 4.42-4.75 (m, 3H), 7.05-7.15 (m, 2H), 7.18-7.25 (m, 3H), 7.42 (d,J=8.4 Hz, 2H), 7.70-7.75 (m, 2H); MS m/z 576.1 (M+H).

Example 1656-(2-(R)-cyclopropylmethyl-3-(S)-hydroxy-1-oxopentyl)amino-4-benzyl-1-[(4-chlorophenyl)sulfonyl]-hexahydro-5H-1,4-diazepin-5-one.¹H NMR (300 MHz, CDCl₃) δ: −0.1-0.17 (m, 2H), 0.3-0.45 (m, 2H), 0.5-0.65(m, 1H), 0.82-0.95 (m, 3H), 1.28-1.70 (m, 5H), 2.25-2.35 (m, 1H),2.40-2.55 (m, 1H), 2.58-2.80 (m, 2H), 3.15-3.25 (m, 1H), 3.32-3.45 (m,1H), 3.62-3.78 (m, 2H), 4.02-4.18 (m, 1H), 4.42-4.75 (m, 3H), 7.05-7.15(m, 2H), 7.18-7.25 (m, 3H), 7.42 (d, J=9.4 Hz, 2H), 7.70-7.75 (m, 2H);MS m/z 548.1 (M+H). Example 166(2R,3S)-2-(cyclopropylmethyl)-N-(1-([3-(4-fluorophenoxy)phenyl]methyl)-2-oxo(3H,4H, 5H-benzo[f]azaperhydroepin-3-yl))-3-hydroxyheptanamide. MS (ESI):559 (M+H). Example 167(2R,3S)-2-(cyclopropylmethyl)-3-hydroxy-N-[2-oxo-1-benzyl(3H, 4H,5H-benzo f]azaperhydroepin-3-yl)]heptanamide. MS (ESI): 449 (M+H).Example 1683-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-benzylpiperizin-1-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 546 (M+H). Example 1693-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-methanesulfonyl-piperazin-1-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 534 (M+H). Example 1703-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 470 (M+H). Example 1713-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-acetylpiperazin-1-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 498 (M+H). Example 1723-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-([4-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperazin-1-yl]-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 615 (M+H). Example 1733-(R,S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-benzoylpiperazin-1-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.MS (ESI): 560 (M+H). Example 1744-[3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxy-heptanoylamino)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-piperazine-1-carboxylicacid tert-butyl ester. MS (ESI): 556 (M+H). Example 1753-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-pyridinylmethylN-oxide)-5-(4-trifluoromethyl)phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-N-oxide.MS (ESI): 625.6 (M+H).

Chromatography Notes:

-   Note a: epimeric mixture at BZD.-   Note b: 1^(st) eluting peak on CHIRALPAK AD chiral column with    10-35% i-PrOH/hexane.-   Note c: 2^(nd) eluting peak on CHIRALPAK AD chiral column with    10-35% i-PrOH/hexane.-   Note d: 1^(st) eluting peak on CHIRALCEL OD chiral column with    2/200/800 ratio of MeOH/i-PrOH/Hexane.-   Note e: 2^(nd) eluting peak on CHIRALCEL OD chiral column with    2/200/800 ratio of MeOH/i-PrOH/Hexane.-   Note f: 1^(st) eluting peak on silica gel column with 2%    MeOH/CH₂Cl₂.-   Note g: 2^(nd) eluting peak on silica gel column with 2% MeOH/CH₂Cl₂-   Note k: made from BZD-amine which in Cbz protected form was the    2^(nd) eluting peak on CHIRALPAK AD column with acetonitrile.-   Note m: made from BZD-amine which in Cbz protected form was the    1^(st) eluting peak on CHIRALPAK AS with methanol.-   Note n: made from BZD-amine which was the 1^(st) eluting peak on    CHIRALPAK AS with 0.1% diethylamine/methanol.-   Note o: made from BZD-amine which was the 2^(nd) eluting peak on    CHIRALPAK AS with 0.1% diethylamine/methanol.-   Note h: made from BZD-amine which was the 1^(st) eluting peak on    CHIRALPAK AD column with 0.1% diethylamine/MeOH.-   Note i: made from BZD-amine which in Cbz protected form was the    1^(st) eluting peak on CHIRALPAK AD column with acetonitrile.-   Note l: made from BZD-amine which in Cbz protected was the 1^(st)    eluting peak on CHIRALCEL OJ with 1:4 of hexane/ethanol.-   Note j: 1^(st) eluting peak on CHIRALPAK AD column with    acetonitrile/water.-   Note p: 2^(nd) eluting peak on CHIRALPAK AD column with    acetonitrile/water.-   Note q: 1^(st) eluting peak on CHIRALCEL OD with 10%    i-propanol/hexane.-   Note r: 2^(nd) eluting peak on CHIRALCEL OD with 10%    i-propanol/hexane.-   Note s: made from bisbenazapine amine which was the 1^(st) peak on    CHIRALCEL OD with 20% i-PrOH/hexane with diethylamine.-   Note t: made from BZD-amine which was the 2^(nd) eluting peak on    CHIRALPAK AD column with 0.1% diethylamine/MeOH.-   Note w: derived from Example 93 by treatment with TFA.-   Note x: derived from Example 88 by treatment with TFA.-   Note u: 2^(nd) eluting peak on silica gel column with 30-80%    EtOAc/hexane.-   Note v: 1^(st) eluting peak on silica gel column with 30-80%    EtOAc/hexane.-   Note y: derived from Example 89 by treatment with TFA.-   Note z: derived from Example 89 by treatment with TFA.-   Note aa: 1^(st) eluting peak on CHIRALPAK AD with 20:80 of    water/MeCN.-   Note bb: 2^(nd) eluting peak on CHIRALPAK AD with 20:80 of    water/MeCN.-   Note cc: made from BZD-amine which in Cbz protected form was the    2^(nd) eluting peak on CHIRALCEL OD column with 1/300/700 ratio of    diethtlamine/EtOH/CO₂.-   Note dd: made from BZD-amine which in Cbz protected form was the    1^(st) eluting peak on CHIRALCEL OD column with 1/300/700 ratio of    diethtlamine/EtOH/CO₂.

Tables 1-8 below provide representative Examples of the compounds ofFormula (I) of the present invention.

TABLE 1

Mass Ex. # Q R⁵ R¹¹ R¹³ (M + H)  1 phenethyl cyclo- phenyl H 524 pentyl-methyl  2 phenethyl cyclo- 4-F-phenyl H 542 pentyl- methyl  3 phenethylbenzyl phenyl H 532  4 phenethyl i-propyl phenyl H 484  5 3,5-diF-cyclo- phenyl H 562 phenoxymethyl pentyl- methyl  6 3,5-diF- i-butylphenyl H 536 phenoxymethyl  7 phenoxymethyl cyclo- phenyl Cl 560 pentyl-methyl  8 phenoxymethyl i-butyl 2-F-phenyl Cl 552  9 cyclohexyl- methylphenyl H 464 oxymethyl 10 cyclohexyl- i-butyl phenyl H 506 oxymethyl 11phenoxymethyl methyl phenyl Cl 492 12 phenoxymethyl i-butyl phenyl Cl534 13 cyclohexyl- benzyl phenyl Cl 574 oxymethyl 14 cyclohexyl- cyclo-phenyl Cl 566 oxymethyl pentyl- methyl 15 cyclohexyl- i-butyl phenyl Cl540 oxymethyl 16 cyclohexyl- i-propyl phenyl Cl 526 oxymethyl 174-CF₃-benzyl- methoxy phenyl Cl 590 oxymethyl 18 2,4-diF-benzyl- methylphenyl Cl 542 oxymethyl 20 benzyloxymethyl vinyl phenyl Cl 536 21cyclohexyl- methyl phenyl Cl 498 oxymethyl 23 phenethyl i-butyl phenyl H498 24 cyclopropyl i-butyl phenyl H 434 25a n-butyl i-butyl phenyl H 45025b n-butyl i-butyl phenyl H 450 25c n-butyl i-butyl phenyl H 450 26n-hexyl i-butyl phenyl H 478 27 n-propyl i-butyl phenyl H 436 28 benzyli-butyl phenyl H 484 29 phenethyl methyl phenyl H 442 30 phenpropylmethyl phenyl H 470 31 methyl i-butyl phenyl H 408 32 n-pentyl i-butylphenyl H 464 33 n-butyl methyl phenyl H 408 34 phenyl methyl phenyl H428 35 2,2-dimethyl- methyl phenyl H 422 propyl 36 n-propyl methylphenyl H 394 37 4-propoxyphenyl methyl phenyl H 486 25a: the chiralcarbon of the benzodiazepine ring is racemic. 25b: the chiral carbon ofthe benzodiazepine ring is (R). 25c: the chiral carbon of thebenzodiazepine ring is (S).

TABLE 2

Ex. # Q

38 n-butyl 3-phenoxybenzyl 39 3,5-diF-phenethyl 3-phenoxybenzyl 40cyclopentylmethyl 3-phenoxybenzyl 41 n-butyl 5-bromo-3-pyridinyl 118n-butyl 3-(phenyl)amino-benzyl 141 n-butyl 3-{[(4-Me-phenyl)sulfonyl]-amino}phenyl)methyl

TABLE 3

Ex. # Q R⁵ R¹¹ R¹³ 42 n-butyl cyclopropylmethyl 2-F-phenyl H 43 n-butylcyclopropylmethyl azapan-1-yl H 44 3,5-diF- cyclopropylmethylpyridin-2-yl H phenethyl 45 n-butyl cyclopropylmethyl 4-Cl-phenyl H 46n-butyl cyclopropylmethyl 3-F-phenyl H 47 n-butyl cyclopropylmethyl4-MeO-phenyl H 48 cyclopentyl cyclopropylmethyl phenyl H methyl 49but-3-enyl cyclopropylmethyl phenyl H 50 but-3-enyl cyclopropylmethyl4-CF₃-phenyl H 51 2-(3,5-dimethyl cyclopropylmethyl phenyl Hisoxazol-4-yl)- ethyl 52 n-butyl cyclopropylmethyl phenyl Cl 53 n-butylcyclopropylmethyl pyridin-2-yl H 54 n-butyl cyclopropylmethyl 4-F-phenylH 55 n-butyl cyclopropylmethyl 4-CF₃-phenyl H 56 2-cyclopentyl-cyclopropylmethyl pyridin-2-yl H ethyl 57 n-butyl i-butyl 4-CF₃-phenyl H58 2-(thiophen-2- cyclopropylmethyl phenyl H yl)-ethyl 592-(furan-2-yl)- cyclopropylmethyl phenyl H ethyl 60 2-cyclopentyl-cyclopropylmethyl 4-F-phenyl H ethyl 61 3,5-diF- cyclopropylmethylphenyl H phenethyl 62 n-butyl cyclopropylmethyl phenyl H 63 n-butylthiophen-2-yl- phenyl H methyl 64 n-butyl cyclopropylmethyl phenyl MeO65 n-butyl cyclobutylmethyl phenyl H 66 n-butyl 3,5-diF-phenyl- phenyl Hmethyl 67 n-butyl furan-2-yl-methyl phenyl H 68 phenethylcyclopropylmethyl 4-F-phenyl H 69 phenethyl cyclopropylmethylpyridin-2-yl H 70 n-butyl i-butyl 4-F-phenyl H 71 phenethylcyclopropylmethyl phenyl H 72 2-furan-2-yl- cyclopropylmethyl4-CF₃-phenyl H ethyl 73 2-cyclopentyl- cyclopropylmethyl 4-CF₃-phenyl Hethyl 74 n-pentyl cyclopropylmethyl 4-CF₃-phenyl H 75 n-hexylcyclopropylmethyl 4-CF₃-phenyl H 76 n-butyl cyclopropylmethyl4-CF₃-pyridin- H 2-yl 77 n-butyl cyclobutylmethyl 4-CF₃-phenyl H 78n-butyl cyclopentylmethyl 4-CF₃-phenyl H 79 n-butyl cyclopropylmethyl4-methyl- H pyridin-2-yl 80 n-butyl cyclopropylmethyl 4-methyl- Hpyridin-2-yl 81 methyl cyclopentylmethyl 4-CF₃-phenyl H 82 n-butylbut-3-enyl phenyl H 83 n-butyl 3-methyl-butyl phenyl H 84 n-butyl ethylphenyl H 85 n-butyl propyl phenyl H 86 n-butyl n-butyl phenyl H 871-(S)-amino- methyl 2-F-phenyl Cl phenethyl 88 1-(S)-(BOC-NH)- methyl2-F-phenyl Cl phenethyl 89 N-BOC- methyl 2-F-phenyl Cl pyrrolidin-2-(R)-yl 90 pyrrolidin-2- methyl 2-F-phenyl Cl (R)-yl 91 benzyloxy-methyli-propyl phenyl Cl 119 n-butyl cyclopropylmethyl cyclopentyl H 120n-butyl cyclopropylmethyl benzyl H 122 n-butyl cyclopropylmethylcycloheptyl H 128 n-butyl cyclopropylmethyl N,N-dibutyl- H amino 133n-butyl i-butyl homopiperidino H 134 n-butyl i-butyl spiro-cyclo- Hpentyl

TABLE 4

Ex. # Q R⁵ R¹¹ R¹³ 92 1-(S)-amino- Methyl 2-F-phenyl Cl phenethyl 931-(S)-(BOC-NH)- Methyl 2-F-phenyl Cl phenethyl 100 n-butylcyclopropylmethyl 4-CF₃-phenyl H 101 n-butyl cyclopropylmethyl4-CF₃-phenyl H

TABLE 5A

Ex. # Q R²

R¹¹ 94 n-butyl H methyl thiazol-2-yl 95 n-butyl H cyclopropylmethylthiazol-2-yl 96 n-butyl H cyclopropylmethyl 4-CF₃-phenyl 97 n-butyl Hbenzyl 4-CF₃-phenyl 98 n-butyl H 3-phenoxy-benzyl 4-CF₃-phenyl 99n-butyl H 3-pyridinyl-methyl 4-CF₃-phenyl 105 n-butyl Me methyl4-CF₃-phenyl 106 n-butyl H 3-phenoxy-benzyl methyl 107 n-butyl H benzylmethyl 121 n-butyl H n-butyl benzyl 123 n-butyl H benzyl cycloheptyl 124n-butyl H n-butyl cycloheptyl 125 n-butyl H 2-pyridinyl-methyl4-CF₃-phenyl 126 n-butyl H 3-pyridinyl-methyl 2-F-phenyl 129 n-butyl Hn-butyl t-butyl 130 n-butyl H 2-oxo-3,3- n-butyl dimethylbutyl 131n-butyl H benzyl t-butyl 132 n-butyl H 2-pyridinyl-methyl n-butyl 137n-butyl H n-butyl i-propyl 138 n-butyl H benzyl i-propyl 139 n-butyl H3-{[(4-Me-phenyl) methyl sulfonyl]amino}- phenyl)methyl 140 n-butyl Hmethyl t-butyl 145 n-butyl H benzyl 2,2-dimethylpropyl 146 n-butyl Hn-butyl n-butyl 147 n-butyl H benzyl n-butyl 148 n-butyl H methyl3,4-dihydro-1H- isoquinolin-2-yl 149 n-butyl H methyl 2,2-dimethylpropyl151 n-butyl H 2-ethylbutyl n-butyl 152 n-butyl H methyl 1-pyrrolidinyl154 n-butyl H 3-hydroxypropyl t-butyl 155 n-butyl H methyl ethoxy 156n-butyl H n-butyl 2,2-dimethylpropyl 157 n-butyl H N-oxide-2-4-CF₃-phenyl pyridinylmethyl 158 n-butyl H N-oxide-3- 4-CF₃-phenylpyridinylmethyl 159 ethyl H 3-pyridinylmethyl 4-CF₃-phenyl 160 n-butyl H2-(diethylamino)ethyl 4-CF₃-phenyl 161 ethyl H N-oxide-3- phenylpyridinylmethyl

TABLE 5B

Ex. # Q R²

R¹¹ 102 n-butyl H methyl 4-CF₃-phenyl

TABLE 5C

Ex. # Q R²

R¹¹ 103 n-butyl H methyl 4-CF₃-phenyl 104 n-butyl H methyl 4-CF₃-phenyl127 ethyl H 3-pyridinyl-methyl 4-CF₃-phenyl

TABLE 5D

Ex. # Q R¹¹ 142 n-butyl 1-piperazinyl 168 n-butyl 4-benzylpiperazin-1-yl169 n-butyl 4 -methanesulfonyl-piperazin-1-yl 170 n-butyl4-methylpiperazin-1-yl 171 n-butyl 4-acetylpiperazin-1-yl 172 n-butyl4-(3,5-dimethyl-isoxazole-4-sulfonyl)- piperazin-1-yl 173 n-butyl4-benzoylpiperazin-1-yl 174 n-butyl 4-(t-butoxycarbonyl)-piperazin-1-yl

TABLE 6

Ex. # R³ Q R⁵/R^(5a) R¹¹ R¹³ 108 acetyl n-butyl R⁵ = i-butyl 4-F-phenylH R^(5a) = H 109 methyl 2-cyclo- R⁵ = cyclopropyl- phenyl H pentyl-methyl ethyl R^(5a) = H 113 H n-butyl CR⁵R^(5a) = 4-F-phenyl H1,1-cyclohexyl 162 H n-butyl R⁵ = cyclopropyl- methyl Br methyl R^(5a) =H

TABLE 7

Ex. # Q

R¹⁰ 163 n-butyl benzyl benzyl 164 n-butyl benzyl (4-chlorophenyl)sulfonyl 165 ethyl benzyl (4-chlorophenyl) sulfonyl

TABLE 8

Ex. # Q Z—Y—X—W— 114 n-butyl methyl 115 n-pentyl methyl 116 n-hexylmethyl 117 2-(furan-2-yl)-ethyl methyl 143 n-butyl 2-diethylaminoethyl144 n-butyl 3-hydroxypropyl 150 n-butyl n-butyl 153 n-butyl benzyl

TABLE 9

Ex. # Q Z—Y—X—W— 166 n-butyl (4-fluorophenoxy)benzyl 167 n-butyl benzyl

TABLE 10

Ex. # Q Z—Y—X—W— R¹¹ 175 n-butyl N-oxide-3- 4-CF₃-phenyl pyridinylmethyl

Utility

Aβ production has been implicated in the pathology of Alzheimer'sDisease (AD). The compounds of the present invention have utility forthe prevention and treatment of AD by inhibiting Aβ production. Methodsof treatment target formation of Aβ production through the enzymesinvolved in the proteolytic processing of β amyloid precursor protein.Compounds that inhibit β or γsecretase activity, either directly orindirectly, control the production of Aβ. Such inhibition of β orγsecretases reduces production of Aβ, and is expected to reduce orprevent the neurological disorders associated with Aβ protein, such asAlzheimer's Disease.

Cellular screening methods for inhibitors of Aβ production, testingmethods for the in vivo suppression of Aβ production, and assays for thedetection of secretase activity are known in the art and have beendisclosed in numerous publications, including PCT publication number WO98/22493, EPO publication number 0652009, U.S. Pat. No. 5,703,129 andU.S. Pat. No. 5,593,846; all hereby incorporated by reference.

The compounds of the present invention have utility for the preventionand treatment of disorders involving Aβ production, such ascerebrovascular disorders.

Compounds of the present invention have been shown to inhibit Aβproduction, as determined by the secretase inhibition assay describedbelow.

Compounds of the present invention have been shown to inhibit Aβproduction, utilizing the C-terminus β amyloid precursor proteinaccumulation assay described below.

Compounds of Formula (I) are expected to possess γ-secretase inhibitoryactivity. The γ-secretase inhibitory activity of the compounds of thepresent invention is demonstrated using assays for such activity, forexample, using the assay described below. Compounds of the presentinvention have been shown to inhibit the activity of γ-secretase, asdetermined by the Aβ immunoprecipitation assay.

Compounds provided by this invention should also be useful as standardsand reagents in determining the ability of a potential pharmaceutical toinhibit Aβ production. These would be provided in commercial kitscomprising a compound of this invention.

As used herein “μg” denotes microgram, “mg” denotes milligram, “g”denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L”denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM”denotes millimolar, “M” denotes molar, “nm” denotes nanometer, “SDS”denotes sodium dodecyl sulfate, and “DMSO” denotes dimethyl sulfoxide,and “EDTA” denotes ethylenediaminetetraacetato.

A compound is considered to be active if it has an IC₅₀ or K_(i) valueof less than about 100 μM for the inhibition of Aβ production.

β Amyloid Precursor Protein Accumulation Assay

A novel assay to evaluate the accumulation of Aβ protein was developedto detect potential inhibitors of secretase. The assay uses the N 9 cellline, characterized for expression of exogenous APP by immunoblottingand immunoprecipitation.

The effect of test compounds on the accumulation of Aβ in theconditioned medium is tested by immunoprecipitation. Briefly, N 9 cellsare grown to confluency in 6-well plates and washed twice with 1× Hank'sbuffered salt solution. The cells are starved in methionine/cysteinedeficient media for 30 min, followed by replacement with fresh deficientmedia containing 150 uCi S35 Translabel (Amersham). Test compoundsdissolved in DMSO (final concentration 1%) are added together with theaddition of radiolabel. The cells are incubated for 4 h at 37° C. in atissue culture incubator.

At the end of the incubation period, the conditioned medium is harvestedand pre-cleared by the addition of 5 μl normal mouse serum and 50 ul ofprotein A Sepharose (Pharmacia), mixed by end-over-end rotation for 30minutes at 4° C., followed by a brief centrifugation in a microfuge. Thesupernatant is then harvested and transferred to fresh tubes containing5 ug of a monoclonal antibody (clone 1101.1; directed against aninternal peptide sequence in Aβ) and 50 μl protein A Sepharose. Afterincubation overnight at 4° C., the samples are washed three times withhigh salt washing buffer (50 mM Tris, pH 7.5, 500 mM NaCl, 5 mM EDTA,0.5% Nonidet P-40), three times with low salt wash buffer (50 mM Tris,pH 7.5, 150 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), and three times with10 mM Tris, pH 7.5. The pellet after the last wash is resuspended in SDSsample buffer (Laemmli, 1970) and boiled for 3 minutes. The supernatantis then fractionated on either 10-20% Tris/Tricine SDS gels or on 16.5%Tris/Tricine SDS gels. The gels are dried and exposed to X-ray film oranalyzed by phosphorimaging. The resulting image is analyzed for thepresence of Aβ polypeptides. The steady-state level of Aβ in thepresence of a test compound is compared to wells treated with DMSO (1%)alone. A typical test compound blocks Aβ accumulation in the conditionedmedium, and is therefore considered active, with an IC₅₀ less than 100μM.

C-Terminus β Amyloid Precursor Protein Accumulation Assay

The effect of test compounds on the accumulation of C-terminal fragmentsis determined by immunoprecipitation of APP and fragments thereof fromcell lysates. N 9 cells are metabolically labeled as above in thepresence or absence of test compounds. At the end of the incubationperiod, the conditioned medium are harvested and cells lysed in RIPAbuffer (10 mM Tris, pH 8.0 containing 1% Triton X-100, 1% deoxycholate,0.1% SDS, 150 mM NaCl, 0.125% NaN₃). Again, lysates are precleared with5 ul normal rabbit serum/50 ul protein A Sepharose, followed by theaddition of BC-1 antiserum (15 μl;) and 50 μl protein A Sepharose for 16hours at 4° C. The immunoprecipitates are washed as above, boundproteins eluted by boiling in SDS sample buffer and fractionated byTris/Tricine SDS-PAGE. After exposure to X-ray film or phosphorimager,the resulting images are analyzed for the presence of C-terminal APPfragments. The steady-state level of C-terminal APP fragments iscompared to wells treated with DMSO (1%) alone. A typical test compoundstimulates C-terminal fragment accumulation in the cell lysates, and istherefore considered active, with an IC₅₀ less than 100 μM.

Aβ Immunoprecipitation Assay

This immunoprecipitation assay is specific for γ secretase (i.e.,proteolytic activity required to generate the C-terminal end of Aβeither by direct cleavage or generating a C-terminal extended specieswhich is subsequently further proteolyzed). N 9 cells are pulse labeledin the presence of a reported γ secretase inhibitor (MDL 28170) for 1 h,followed by washing to remove radiolabel and MDL 28170. The media isreplaced and test compounds are added. The cells are chased forincreasing periods of times and A β is isolated from the conditionedmedium and C-terminal fragments from cell lysates (see above). The testcompounds are characterized whether a stabilization of C-terminalfragments is observed and whether Aβ is generated from these accumulatedprecursor. A typical test compound prevents the generation of AD out ofaccumulated C-terminal fragments and is considered active with an IC₅₀less than 100 μM.

Dosage and Formulation

The compounds of the present invention can be administered orally usingany pharmaceutically acceptable dosage form known in the art for suchadministration. The active ingredient can be supplied in solid dosageforms such as dry powders, granules, tablets or capsules, or in liquiddosage forms, such as syrups or aqueous suspensions. The activeingredient can be administered alone, but is generally administered witha pharmaceutical carrier. A valuable treatise with respect topharmaceutical dosage forms is Remington's Pharmaceutical Sciences, MackPublishing.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using dosageforms well known to those of ordinary skill in the pharmaceutical arts.An effective but non-toxic amount of the compound desired can beemployed to prevent or treat neurological disorders related to β-amyloidproduction or accumulation, such as Alzheimer's disease and Down'sSyndrome.

The compounds of this invention can be administered by any means thatproduces contact of the active agent with the agent's site of action inthe body of a host, such as a human or a mammal. They can beadministered by any conventional means available for use in conjunctionwith pharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butgenerally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. An ordinarily skilled physician or veterinarian canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter, or arrest the progress of the condition.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three, or four times daily.

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wallknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittant throughout the dosageregimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients, orcarriers (collectively referred to herein as carrier materials) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor β-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamallar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance. In general, water, a suitableoil, saline, aqueous dextrose (glucose), and related sugar solutions andglycols such as propylene glycol or polyethylene glycols are suitablecarriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

1. A compound of the formula (I):

or a pharmaceutically acceptable salt form thereof, wherein: Q is Q¹,(C₁-C₃ alkylene)-O-Q¹, (C₁-C₃ alkylene)-S-Q¹, (C₁-C₃ alkylene)-S(═O)-Q¹,(C₁-C₃ alkylene)-S(═O)₂-Q¹, or (C₁-C₃ alkylene)-N(R²⁰)-Q¹; Q¹ is C₁-C₈alkyl substituted with 0-3 R^(1a); C₂-C₈ alkenyl substituted with 0-3R^(1a); C₂-C₈ alkynyl substituted with 0-3 R^(1a); C₃-C₁₀ cycloalkylsubstituted with 0-3 R^(1b); C₃-C₁₀ carbocycle substituted with 0-3R^(1b); aryl substituted with 0-3 R^(1b); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(1b); R^(1a), at each occurrence, isindependently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶,CF₃; C₃-C₁₀ carbocycle substituted with 0-3 R^(1b); aryl substitutedwith 0-3 R^(1b); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(1b); R^(1b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—, and(C₁-C₆ alkyl)-O—C(═O)—; R² is H, methyl, ethyl, propyl, or butyl; R³ isH, C₁-C₆ alkyl, —C(═O)(C₁-C₆ alkyl), —C(═S)(C₁-C₆ alkyl), or—C(═O)NR²¹R²²; alternatively, R² and OR³ are combined to form C═O orC═N—OH; R⁵ is H, OR¹⁴; C₁-C₆ alkyl substituted with 0-3 R^(5b); C₁-C₆alkoxy substituted with 0-3 R^(5b); C₂-C₆ alkenyl substituted with 0-3R^(5b); C₂-C₆ alkynyl substituted with 0-3 R^(5b); C₃-C₁₀ cycloalkylsubstituted with 0-3 R^(5c); C₃-C₁₀ carbocycle substituted with 0-3R^(5c); aryl substituted with 0-3 R^(5c); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3R^(5c); R^(5a) is H, C₁-C₄ alkyl, or C₂-C₄ alkenyl;alternatively, R⁵ and R^(5a) may be combined to form a 3-7 memberedcycloalkyl ring substituted with 0-3 R^(5c); optionally the cycloalkylring formed by combining R⁵ and R^(5a) may be benzo fused, wherein thebenzo fused ring may be substituted with 0-3 R^(5c); R^(5b), at eachoccurrence, is independently selected from: H, C₁-C₆ alkyl, CF₃, OR¹⁴,Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, C₁-C₄ haloalkyl-S—, C₃-C₁₀ cycloalkyl substituted with 0-3R^(5c); C₃-C₁₀ carbocycle substituted with 0-3 R^(5c); aryl substitutedwith 0-3 R^(5c); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(5c); R^(5c), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁶ isH or C₁-C₆ alkyl; W is —(CR⁸R^(8a))_(p)—; p is 0, 1, 2, 3, or 4; R⁸ andR^(8a), at each occurrence, are independently selected from H, F, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈ cycloalkyl; X is a bond;aryl substituted with 0-3 R^(Xb); C₃-C₁₀ cycloalkyl substituted with 0-3R^(Xb); C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or 5 to 10membered heterocycle substituted with 0-2 R^(Xb); R^(Xb), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; Y isa bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; t is 0, 1, 2, or 3; u is0, 1, 2, or 3; R⁹ and R^(9a), at each occurrence, are independentlyselected from H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; V is a bond,—C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—, —C(═O)NR^(19b)—,—NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—, —S(═O)₂NR^(19b)—, —C(═O)O—, or—OC(═O)—; Z is H; C₁-C₈ alkyl substituted with 0-2 R¹²; C₂-C₄ alkenylsubstituted with 0-2 R¹²; C₂-C₄ alkynyl substituted with 0-2 R¹²; arylsubstituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with 0-4R^(12b); or 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b); Ring B is

wherein said benzo fused radical or 5 to 6 membered heteroaryl fusedradical is substituted with 0-3 R¹³; R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷,C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷; C₁-C₆ alkyl substituted with 0-2R^(10a); aryl substituted with 0-4 R^(10b); C₃-C₁₀ carbocyclesubstituted with 0-3 R^(10b); or 5 to 10 membered heterocycle containing1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 10 membered heterocycle is optionally substituted with 0-3R^(10b); R^(10a), at each occurrence, is independently selected from H,C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃; arylsubstituted with 0-4 R^(10b); C₃-C₁₀ carbocycle substituted with 0-3R^(10b); or 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is optionally substituted with 0-3 R^(10b);R^(10b), at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹² at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,—C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;aryl substituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with0-4 R^(12b); or 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(12b); R^(12b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³,at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl,C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴, at eachoccurrence, is independently selected from H, phenyl, benzyl, C₁-C₆alkyl, and C₂-C₆ alkoxyalkyl; R^(14a) is H, phenyl, benzyl, or C₁-C₆alkyl; R¹⁵, at each occurrence, is independently selected from H, C₁-C₆alkyl, phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—; R¹⁶, at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, phenyl, benzyl,phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆ alkyl)-O—C(═O)— and (C₁-C₆alkyl)-S(═O)₂—; alternatively, —NR¹⁵R¹⁶ may be a heterocyclic ringselected from the group piperidinyl, morpholinyl, thiomorpholinyl,pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; R¹⁷is H, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl, aryl substituted by 0-4R^(17a), or aryl-CH₂— wherein said aryl is substituted by by 0-4R^(17a); R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(═O)CH₃,S(═O)₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl; R¹⁸, at each occurrence,is independently selected from H, C₁-C₆ alkyl, phenyl, benzyl,phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;alternatively, —NR¹⁸R¹⁹ may be a heterocyclic ring selected from thegroup: piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,homopiperidinyl, piperazinyl, and N-methylpiperizinyl; wherein saidheterocyclic ring is substituted with 0-3 R^(11b)—; R¹⁹, at eachoccurrence, is independently selected from H, OH, C₁-C₆ alkyl, phenyl,benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;R^(19b), at each occurrence, is independently selected from H and C₁-C₆alkyl; R²⁰ is H, OH, C₁-C₄ alkyl, phenyl, benzyl, or phenethyl; R²¹, ateach occurrence, is independently selected from H, C₁-C₆ alkyl, phenyl,benzyl, and phenethyl; and R²², at each occurrence, is independentlyselected from H, C₁-C₆ alkyl, phenyl, benzyl, and phenethyl.
 2. Acompound of Formula (I) according to claim 1,

or a pharmaceutically acceptable salt form thereof, wherein: Q is Q¹,(C₁-C₃ alkylene)-O-Q¹, (C₁-C₃ alkylene)-S-Q¹, (C₁-C₃ alkylene)-S(═O)-Q¹,(C₁-C₃ alkylene)-S(═O)₂-Q¹, or (C₁-C₃ alkylene)-N(R²⁰)-Q¹; Q¹ is C₁-C₆alkyl substituted with 0-3 R^(1a); C₂-C₆ alkenyl substituted with 0-3R^(1a); C₂-C₆ alkynyl substituted with 0-3 R^(1a); C₃-C₁₀ cycloalkylsubstituted with 0-3 R^(1b); C₃-C₁₀ carbocycle substituted with 0-3R^(1b); aryl substituted with 0-3 R^(1b); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(1b); R^(1a), at each occurrence, isindependently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶,CF₃; C₃-C₁₀ carbocycle substituted with 0-3 R^(1b); aryl substitutedwith 0-3 R^(1b); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(1b); R^(1b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—, and(C₁-C₆ alkyl)-O—C(═O)—; R² is H, methyl, ethyl, propyl, or butyl; R³ isH, C₁-C₄ alkyl, —C(═O)(C₁-C₄ alkyl), —C(═S)(C₁-C₄ alkyl), or—C(═O)NR²¹R²²; R⁵ is H, OR¹⁴; C₁-C₆ alkyl substituted with 0-3 R^(5b);C₁-C₆ alkoxy substituted with 0-3 R^(5b); C₂-C₆ alkenyl substituted with0-3 R^(5b); C₂-C₆ alkynyl substituted with 0-3 R^(5b); C₃-C₁₀ cycloalkylsubstituted with 0-3 R^(5c); C₃-C₁₀ carbocycle substituted with 0-3R^(5c); aryl substituted with 0-3 R^(5c); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(5c); R^(5a) is H, C₁-C₄ alkyl, or C₂-C₄ alkenyl;alternatively, R⁵ and R^(5a) may be combined to form a 3-7 memberedcycloalkyl ring substituted with 0-3 R^(5c); R^(5b), at each occurrence,is independently selected from: H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I,═O, CN, NO₂, NR¹⁵R¹⁶, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, andC₁-C₄ haloalkyl-S—, C₃-C₁₀ cycloalkyl substituted with 0-3 R^(5c);C₃-C₁₀ carbocycle substituted with 0-3 R^(5c); aryl substituted with 0-3R^(5c); and 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(5c); R^(5c), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R⁶ isH, methyl, or ethyl; W is —(CR⁸R^(8a))_(p)—; p is 0, 1, or 2; R⁸ andR^(8a), at each occurrence, are independently selected from H, F,methyl, and ethyl; X is a bond; phenyl substituted with 0-3 R^(Xb);C₃-C₆ cycloalkyl substituted with 0-3 R^(Xb); or 5 to 6 memberedheterocycle substituted with 0-2 R^(Xb); R^(Xb), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; Y is a bond or—(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; t is 0, 1, or 2; u is 0, 1, or 2;R⁹ and R^(9a), at each occurrence, are independently selected from H, F,methyl, and ethyl; V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—,—N(R¹⁹)—, —C(═O)NH—, —NHC(═O)—, —NHS(═O)₂—, or —S(═O)₂NH—; Z is H, halo;C₁-C₄ alkyl substituted with 0-2 R¹²; C₂-C₄ alkenyl substituted with 0-2R¹²; C₂-C₄ alkynyl substituted with 0-2 R¹²; aryl substituted with 0-4R^(12b); C₃-C₆ carbocycle substituted with 0-4 R^(12b); or 5 to 6membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycleis substituted with 0-3 R^(12b); Ring B is

wherein said benzo fused radical or 5 to 6 membered heteroaryl fusedradical is substituted with 0-3 R¹³; R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷,C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷; C₁-C₆ alkyl substituted with 0-2R^(10a); aryl substituted with 0-4 R^(10b); C₃-C₁₀ carbocyclesubstituted with 0-3 R^(10b); or 5 to 10 membered heterocycle containing1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 10 membered heterocycle is optionally substituted with 0-3R^(10b); R^(10a), at each occurrence, is independently selected from H,C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or arylsubstituted with 0-4 R^(10b); R^(10b), at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br,I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl-S—; R¹² at each occurrence, is independently selected from H,OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄ haloalkyl-S—; aryl substituted with 0-4 R^(12b);C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(12b); R^(12b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, T, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³, at eachoccurrence, is independently selected from H, OH, C₁-C₆ alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴, at eachoccurrence, is independently selected from H, phenyl, benzyl, C₁-C₆alkyl, and C₂-C₆ alkoxyalkyl; R¹⁵, at each occurrence, is independentlyselected from H, C₁-C₆ alkyl, phenyl, benzyl, phenethyl, (C₁-C₆alkyl)—C(═O)—, (C₁-C₆ alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—; R¹⁶, ateach occurrence, is independently selected from H, OH, C₁-C₆ alkyl,phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆ alkyl)-O—C(═O)—and (C₁-C₆ alkyl)-S(═O)₂—; alternatively, —NR¹⁵R¹⁶ may be a heterocyclicring selected from the group piperidinyl, morpholinyl, thiomorpholinyl,pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; R¹⁷is H, aryl, aryl-CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; R¹⁸, at eachoccurrence, is independently selected from H, C₁-C₆ alkyl, phenyl,benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—; R¹⁹,at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl,phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆alkyl)-S(═O)₂—; alternatively, —NR¹⁸R¹⁹ may be a heterocyclic ringselected from the group piperidinyl, morpholinyl, thiomorpholinyl,pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; R²⁰is H, OH, C₁-C₄ alkyl, phenyl, benzyl, or phenethyl; R²¹, at eachoccurrence, is independently selected from H, C₁-C₆ alkyl, phenyl,benzyl, and phenethyl; and R²², at each occurrence, is independentlyselected from H, C₁-C₆ alkyl, phenyl, benzyl, and phenethyl.
 3. Acompound of claim 1, of Formula (Ia):

or a pharmaceutically acceptable salt form thereof, wherein: Q is Q¹,(C₁-C₃ alkylene)-O-Q¹, (C₁-C₃ alkylene)-S-Q¹, (C₁-C₃ alkylene)-S(═O)-Q¹,(C₁-C₃ alkylene)-S(═O)₂-Q¹, or (C₁-C₃ alkylene)-N(R²⁰)-Q¹; Q¹ is C₁-C₆alkyl substituted with 0-3 R^(1a); C₂-C₆ alkenyl substituted with 0-3R^(1a); C₂-C₆ alkynyl substituted with 0-3 R^(1a); C₃-C₁₀ cycloalkylsubstituted with 0-3 R^(1b); C₃-C₁₀ carbocycle substituted with 0-3R^(1b); aryl substituted with 0-3 R^(1b); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(1b); R^(1a), at each occurrence, isindependently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶,CF₃; C₃-C₁₀ carbocycle substituted with 0-3 R^(1b); aryl substitutedwith 0-3 R^(1b); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(1b); R^(1b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂NR¹⁵, R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—, and(C₁-C₆ alkyl)-O—C(═O)—; R² is H, methyl, or ethyl; R⁵ is H, OR¹⁴; C₁-C₆alkyl substituted with 0-3 R^(5b); C₁-C₆ alkoxy substituted with 0-3R^(5b); C₂-C₆ alkenyl substituted with 0-3 R^(5b); C₂-C₆ alkynylsubstituted with 0-3 R^(5b); C₃-C₁₀ cycloalkyl substituted with 0-3R^(5c); C₃-C₁₀ carbocycle substituted with 0-3 R^(5c); aryl substitutedwith 0-3 R^(5c); or 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3R^(5c); R^(5a) is H,C₁-C₄ alkyl, or C₂-C₄ alkenyl; R^(5b), at each occurrence, isindependently selected from: H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I,═O, CN, NO₂, NR¹⁵R¹⁶, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, andC₁-C₄ haloalkyl-S—, C₃-C₁₀ cycloalkyl substituted with 0-3 R^(5c);C₃-C₁₀ carbocycle substituted with 0-3 R^(5c); aryl substituted with 0-3R^(5c); and 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(5c); R^(5c), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; W is—(CR⁸R^(8a))_(p)—; p is 0, 1, or 2; R⁸ and R^(8a), at each occurrence,are independently selected from H, F, methyl, and ethyl; X is a bond;phenyl substituted with 0-3 R^(Xb); C₃-C₆ cycloalkyl substituted with0-3 R^(Xb); or 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-2 R^(Xb); R^(Xb), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; Y isa bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; t is 0, 1, or 2; u is 0,1, or 2; R⁹ and R^(9a), at each occurrence, are independently selectedfrom H, F, methyl, and ethyl; V is a bond, —C(═O)—, —O—, —S—, —S(═O)—,—S(═O)₂—, —N(R¹⁹)—, —C(═O)NH—, or —NHC(═O)—; Z is H, halo; C₁-C₄ alkylsubstituted with 0-2 R¹²; C₂-C₄ alkenyl substituted with 0-2 R¹²; C₂-C₄alkynyl substituted with 0-2 R¹²; aryl substituted with 0-4 R^(12b);C₃-C₆ carbocycle substituted with 0-4 R^(12b); or 5 to 6 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 6 membered heterocycle issubstituted with 0-3 R^(12b); Ring B is

R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;C₁-C₆ alkyl substituted with 0-2 R^(10a); aryl substituted with 0-4R^(10b); C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or 5 to 10membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycleis optionally substituted with 0-3 R^(10b); R^(10a), at each occurrence,is independently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O,CN, NO₂, NR¹⁵R¹⁶, CF₃, or aryl substituted with 0-4 R^(10b); R^(10b), ateach occurrence, is independently selected from H, OH, C₁-C₆ alkyl,C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹² at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,—C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;aryl substituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with0-4 R^(12b); or 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(12b); R^(12b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³,at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl,C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴, at eachoccurrence, is independently selected from H, phenyl, benzyl, C₁-C₆alkyl, and C₂-C₆ alkoxyalkyl; R¹⁵, at each occurrence, is independentlyselected from H, C₁-C₆ alkyl, phenyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, (C₁-C₆ alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—; R¹⁶, ateach occurrence, is independently selected from H, OH, C₁-C₆ alkyl,phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆ alkyl)-O—C(═O)—and (C₁-C₆ alkyl)-S(═O)₂—; alternatively, —NR¹⁵R¹⁶ may be a heterocyclicring selected from the group piperidinyl, morpholinyl, thiomorpholinyl,pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; R¹⁷is H, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl, aryl substituted by 0-4R^(17a), or aryl-CH₂ wherein said aryl is substituted by by 0-4 R^(17a);R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, —NH₂,—N(CH₃)₂, or C₁-C₄ haloalkyl; R¹⁸, at each occurrence, is independentlyselected from H, C₁-C₆ alkyl, phenyl, benzyl, phenethyl, C₁-C₆alkyl)-C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—; R¹⁹, at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, phenyl, benzyl,phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—;alternatively, —NR¹⁸R¹⁹ may be a heterocyclic ring selected from thegroup: piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,homopiperidinyl, piperazinyl, and N-methylpiperizinyl; wherein saidheterocyclic ring is substituted with 0-3 R^(11b)—; and R²⁰ is H, OH,C₁-C₄ alkyl, phenyl, benzyl, or phenethyl.
 4. A compound, according toclaim 3, of Formula (Ia) or pharmaceutically acceptable salt thereof:

wherein: Ring B is

Q is Q¹ or (C₁-C₃ alkyl)-O-Q¹; Q¹ is C₁-C₆ alkyl substituted with 0-3R^(1a); C₂-C₆ alkenyl substituted with 0-3 R^(1a); C₂-C₆ alkynylsubstituted with 0-3 R^(1a); C₃-C₁₀ cycloalkyl substituted with 0-3R^(1b); C₃-C₁₀ carbocycle substituted with 0-3 R^(1b); aryl substitutedwith 0-3 R^(1b); or 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(1b); R^(1a), ateach occurrence, is independently selected from H, C₁-C₆ alkyl, OR¹⁴,Cl, F, Br, I, NR¹⁵R¹⁶, CF₃; C₃-C₁₀ carbocycle substituted with 0-3R^(1b); C₆-C₁₀ aryl substituted with 0-3 R^(1b); and 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(1b); R^(1b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—, and (C₁-C₆alkyl)-O—C(═O)—; R² is H, methyl, or ethyl; R⁵ is H, OR¹⁴; C₁-C₆ alkylsubstituted with 0-3 R^(5b); C₂-C₆ alkenyl substituted with 0-3 R^(5b);C₂-C₆ alkynyl substituted with 0-3 R^(5b); C₃-C₆ cycloalkyl substitutedwith 0-3 R^(5c); C₃-C₆ carbocycle substituted with 0-3 R^(5c); phenylsubstituted with 0-3 R^(5c); or 5 to 7 membered heterocycle containing 1to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 7 membered heterocycle is substituted with 0-3R^(5c); R^(5a)is H, C₁-C₄ alkyl, or C₂-C₄ alkenyl; alternatively, R⁵ and R^(5a) may becombined to form a C₄-C₇ cycloalkyl ring; R^(5b), at each occurrence, isindependently selected from: H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I,═O, CN, NO₂, NR¹⁵R¹⁶, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, andC₁-C₄ haloalkyl-S—, C₃-C₁₀ cycloalkyl substituted with 0-3 R^(5c);C₃-C₁₀ carbocycle substituted with 0-3 R^(5c); C₆-C₁₀ aryl substitutedwith 0-3 R^(5c); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(5c); R^(5c), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; W is—(CR⁸R^(8a))_(p)—; p is 0, 1, or 2; R⁸ and R^(8a), at each occurrence,are independently selected from H, methyl, and ethyl; X is a bond;phenyl substituted with 0-3 R^(Xb); C₃-C₆ cycloalkyl substituted with0-3 R^(Xb); or 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-2 R^(Xb); R^(Xb), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; Y isa bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; t is 0, 1, or 2; u is 0,1, or 2; R⁹ and R^(9a), at each occurrence, are independently selectedfrom H, F, methyl, and ethyl; V is a bond, —C(═O)—, —O—, —S—, —S(═O)—,—S(═O)₂—, —N(R¹⁹)—, —NHC(═O)—, or —C(═O)NH—; Z is H, F, Cl, Br; C₁-C₄alkyl substituted with 0-2 R¹²; C₂-C₄ alkenyl substituted with 0-2 R¹²;C₂-C₄ alkynyl substituted with 0-2 R¹²; aryl substituted with 0-4R^(12b); C₃-C₆ carbocycle substituted with 0-4 R^(12b); or 5 to 6membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycleis substituted with 0-3 R^(12b); R¹⁰ is C(═O)R¹⁷, C(═O)NR¹⁸R¹⁹,S(═O)₂R¹⁷; C₁-C₆ alkyl substituted with 0-2 R^(10a); phenyl substitutedwith 0-3 R^(10b); or 5 to 6 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 6 membered heterocycle is optionally substituted with 0-3 R^(10b);R^(10a), at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or arylsubstituted with 0-3 R^(10b); R^(10b), at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br,I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl-S—; R¹² at each occurrence, is independently selected from H,OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄ haloalkyl-S—; aryl substituted with 0-4 R^(12b);C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(12b); R^(12b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³, at eachoccurrence, is independently selected from H, OH, C₁-C₆ alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴, at eachoccurrence, is independently selected from H, phenyl, benzyl, C₁-C₆alkyl, and C₂-C₆ alkoxyalkyl; R¹⁵, at each occurrence, is independentlyselected from H, C₁-C₆ alkyl, phenyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, (C₁-C₆ alkyl)-O—C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—; R¹⁶, ateach occurrence, is independently selected from H, OH, C₁-C₆ alkyl,phenyl, benzyl, phenethyl, (C₁-C₆ alkyl)-C(═O)—, (C₁-C₆ alkyl)-O—C(═O)—and (C₁-C₆ alkyl)-S(═O)₂—; alternatively, —NR¹⁵R¹⁶ may be a heterocyclicring selected from the group piperidinyl, morpholinyl, thiomorpholinyl,pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; andR¹⁷ is H, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl, aryl substituted by 0-4R^(17a), or aryl-CH₂— wherein said aryl is substituted by by 0-4R^(17a); R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(═O)CH₃,S(═O)₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄ haloalkyl; R¹⁸, at each occurrence,is independently selected from H, C₁-C₆ alkyl, phenyl, benzyl,phenethyl, (C₁-C₆ alkyl)-C(═O)— and (C₁-C₆ alkyl)-S(═O)₂—; R¹⁹, at eachoccurrence, is independently selected from H, OH, methyl, ethyl, propyl,butyl, phenyl, benzyl, and phenethyl; and alternatively, —NR¹⁸R¹⁹ may bea heterocyclic ring selected from the group: piperidinyl, morpholinyl,thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, andN-methylpiperizinyl; wherein said heterocyclic ring is substituted with0-3 R^(11b).
 5. A compound of claim 4 wherein: Q is Q¹; Q¹ is C₁-C₆alkyl substituted with 0-3 R^(1a); C₂-C₆ alkenyl substituted with 0-3R^(1a); C₂-C₆ alkynyl substituted with 0-3 R^(1a); C₃-C₁₀ cycloalkylsubstituted with 0-3 R^(1b); C₃-C₁₀ carbocycle substituted with 0-3R^(1b); aryl substituted with 0-3 R^(1b); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(1b); R^(1a), at each occurrence, isindependently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶,CF₃; C₃-C₁₀ carbocycle substituted with 0-3 R^(1b); aryl substitutedwith 0-3 R^(1b); and 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(1b); R^(1b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl-S—, and(C₁-C₆ alkyl)-O—C(═O)—; R² is H, methyl, or ethyl; R⁵ is H, OR¹⁴; C₁-C₆alkyl substituted with 0-3 R^(5b); C₂-C₆ alkenyl substituted with 0-3R^(5b); or C₂-C₆ alkynyl substituted with 0-3 R^(5b); R^(5a) is H,methyl, ethyl, propyl, butyl, or C₂-C₄ alkenyl; alternatively, R⁵ andR^(5a) may be combined to form a C₄-C₇ cycloalkyl ring; R^(5b), at eachoccurrence, is independently selected from: H, methyl, ethyl, propyl,butyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, NR¹⁵R¹⁶, C₃-C₇ cycloalkylsubstituted with 0-3 R^(5c); C₃-C₇ carbocycle substituted with 0-3R^(5c); phenyl substituted with 0-3 R^(5c); and 5 to 7 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 7 membered heterocycle issubstituted with 0-3 R^(5c); R^(5c), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂haloalkyl, and C₁-C₂ haloalkoxy; W is —(CHR⁸)_(p)—; p is 0 or 1; R⁸ isH, methyl, or ethyl; X is a bond; phenyl substituted with 0-2 R^(Xb);C₅-C₆ cycloalkyl substituted with 0-3 R^(Xb); or 5 to 6 memberedheterocycle containing 1 to 3 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 6 membered heterocycle issubstituted with 0-2 R^(Xb); R^(Xb), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; Y is a bond, V is abond, Z is H, F, Cl, Br, C₁-C₄ alkyl substituted with 0-2 R¹²; C₂-C₄alkenyl substituted with 0-2 R¹²; C₂-C₄ alkynyl substituted with 0-2R¹²; aryl substituted with 0-4 R^(12b); C₃-C₆ carbocycle substitutedwith 0-4 R^(12b); or 5 to 6 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 6 membered heterocycle is substituted with 0-3 R^(12b); R¹⁰ isC(═O)R¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂R¹⁷; C₁-C₆ alkyl substituted with 0-2R^(10a); phenyl substituted with 0-3 R^(10b); or 5 to 6 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 6 membered heterocycle isoptionally substituted with 0-3 R^(10b); R^(10a), at each occurrence, isindependently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN,NO₂, NR¹⁵R¹⁶, CF₃, or aryl substituted with 0-3 R^(10b); R^(10b), ateach occurrence, is independently selected from H, OH, C₁-C₆ alkyl,C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃,S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹² at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶,—C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—;aryl substituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with0-4 R^(12b); or 5 to 10 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 10 membered heterocycle is substituted with 0-3 R^(12b); R^(12b), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³,at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl,C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴, at eachoccurrence, is independently selected from H, phenyl, benzyl, C₁-C₄alkyl, and C₂-C₄ alkoxyalkyl; R¹⁵, at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, andphenethyl; R¹⁶, at each occurrence, is independently selected from H,OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl,CH₃CH₂C(═O)—, CH₃C(═O)—, CH₃CH₂OC(═O)—, CH₃OC(═O)—, CH₃CH₂S(═O)₂— andCH₃S(═O)₂—; R¹⁷ is H, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl; phenylsubstituted by 0-2 R^(17a); or benzyl substituted by 0-2 R^(17a);R^(17a) is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, —NH₂,—N(CH₃)₂, or C₁-C₄ haloalkyl; R¹⁸, at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, andphenethyl; R¹⁹, at each occurrence, is independently selected from H,OH, methyl, ethyl, propyl, and butyl; and alternatively, —NR¹⁸R¹⁹ may bea heterocyclic ring selected from the group: piperidinyl, morpholinyl,thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, andN-methylpiperizinyl; wherein said heterocyclic ring is substituted with0-3 R^(11b).
 6. A compound of claim 5 wherein: Q is Q¹, Q¹ is C₁-C₆alkyl substituted with 0-3 R^(1a); C₂-C₆ alkenyl substituted with 0-3R^(1a); C₂-C₆ alkynyl substituted with 0-3 R^(1a); C₃-C₆ cycloalkylsubstituted with 0-3 R^(1b); phenyl substituted with 0-3 R^(1b); or 5 to6 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycleis substituted with 0-3 R^(1b); R^(1a), at each occurrence, isindependently selected from H, methyl, ethyl, propyl, butyl, OR¹⁴, Cl,F, Br, I, NR¹⁵R¹⁶, CF₃; C₃-C₆ carbocycle substituted with 0-3 R^(1b);phenyl substituted with 0-3 R^(1b); and 5 to 6 membered heterocyclecontaining 1 to 4 heteroatoms selected from nitrogen, oxygen, andsulphur, wherein said 5 to 6 membered heterocycle is substituted with0-3 R^(1b); R^(1b), at each occurrence, is independently selected fromH, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, C₁-C₂ haloalkoxy, (methyl)OC(═O)—, (ethyl)OC(═O)—,(propyl)OC(═O)—, and (butyl)OC(═O)—; R² is H or methyl; R⁵ is H, OR¹⁴;C₁-C₄ alkyl substituted with 0-1 R^(5b); C₂-C₄ alkenyl substituted with0-1 R^(5b); or C₂-C₄ alkynyl substituted with 0-1 R^(5b); R^(5a) is H,methyl, ethyl, propyl, or butyl; alternatively, R⁵ and R^(5a) may becombined to form a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptylring; R^(5b), at each occurrence, is independently selected from: H,methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, Cl, F, ═O, NR¹⁵R¹⁶, C₃-C₇cycloalkyl substituted with 0-3 R^(5c); C₃-C₇ carbocycle substitutedwith 0-3 R^(5c); phenyl substituted with 0-3 R^(5c); and 5 to 7 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 7 membered heterocycle issubstituted with 0-3 R^(5c); wherein said 5 to 7 membered heterocycle isselected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl,thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; R^(5c), ateach occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶,CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl,methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; W is abond, —CH₂—, or —CH(CH₃)—; X is a bond; phenyl substituted with 0-1R^(Xb); C₅-C₆ cycloalkyl substituted with 0-1 R^(Xb); or 5 to 6 memberedheterocycle containing 1 to 3 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 6 membered heterocycle issubstituted with 0-1 R^(Xb); wherein said 5 to 6 membered heterocycle isselected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl,thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,oxazolyl, and isoxazolyl; R^(Xb), at each occurrence, is independentlyselected from H, OH, Cl, F, Br, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂ haloalkoxy; Y is a bond, V is a bond, Z is H, F,Cl, Br, C₁-C₄ alkyl substituted with 0-2 R¹²; C₂-C₄ alkenyl substitutedwith 0-2 R¹²; C₂-C₄ alkynyl substituted with 0-2 R¹²; aryl substitutedwith 0-4 R^(12b); C₃-C₆ carbocycle substituted with 0-4 R^(12b); or 5 to6 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycleis substituted with 0-3 R^(12b); R¹⁰ is C(═O)R¹⁷, C(═O)NR¹⁸R¹⁹,S(═O)₂R¹⁷; C₁-C₆ alkyl substituted with 0-2 R^(10a); phenyl substitutedwith 0-3 R^(10b); or 5 to 6 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 6 membered heterocycle is optionally substituted with 0-3 R^(10b);R^(10a), at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or arylsubstituted with 0-3 R^(10b); R^(10b), at each occurrence, isindependently selected from H, OH, C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br,I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O) CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl-S—; R¹² at each occurrence, is independently selected from H,OH, Cl, F, Br, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂ haloalkoxy; phenyl substituted with 0-4 R^(12b);C₃-C₆ carbocycle substituted with 0-4 R^(12b); or 5 to 6 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 6 membered heterocycle issubstituted with 0-3 R^(12b); R^(12b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, NR¹⁵R¹⁶, CF₃, acetyl,SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy,ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; R¹³, at eachoccurrence, is independently selected from H, OH, methyl, ethyl, propyl,butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NR¹⁵R¹⁶, and CF₃; R¹⁴,at each occurrence, is independently selected from H, phenyl, benzyl,methyl, ethyl, propyl, and butyl; R¹⁵, at each occurrence, isindependently selected from H, methyl, ethyl, propyl, or butyl; R¹⁶, ateach occurrence, is independently selected from H, OH, methyl, ethyl,propyl, butyl, phenyl, benzyl, and phenethyl; R¹⁸, at each occurrence,is independently selected from H, methyl, ethyl, propyl, butyl, phenyl,benzyl and, phenethyl; and R¹⁹, at each occurrence, is independentlyselected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl and,phenethyl.
 7. A compound or pharmaceutically acceptable salt formthereof of claim 6 wherein: Q is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₂CH₃, —CH(CH₃)₂,—CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃, —CH₂CH₂CF₃,—CH₂CH₂CH₂CF₃, —CH═CH₂, —CH₂CH═CH₂, —CH₂C(CH₃)═CH₂, —CH₂CH═C(CH₃)₂,—CH₂CH₂CH═CH₂, —CH₂CH₂C(CH₃)═CH₂, —CH₂CH₂CH═C(CH₃)₂, cis-CH₂CH═CH(CH₃),cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃), trans-CH₂CH₂CH═CH(CH₃);—C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃), cyclopropyl-, cyclobutyl-, cyclopentyl-,cyclohexyl-, cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—, phenyl-, 2-F-phenyl-,3-F-phenyl-, 4-F-phenyl-, 4-methoxyphenyl-, 4-ethoxyphenyl-,4-propoxyphenyl-, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,(4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—,(4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,(2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—,(3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,(2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—,(3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,(3-Cl-4-F-phenyl) CH₂—, 2-furanyl-CH₂—, 3-furanyl-CH₂—, 2-thienyl-CH₂—,3-thienyl-CH₂—, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—,1-imidazolyl-CH₂—, 2-oxazolyl-CH₂—, 4-oxazolyl-CH₂—, 5-oxazolyl-CH₂—,3-isoxazolyl-CH₂—, 4-isoxazolyl-CH₂—, 5-isoxazolyl-CH₂—, phenyl-CH₂CH₂—,(2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—,(2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl) CH₂CH₂—,(2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,(2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—,(2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—,(2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—,(3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—,(3-F-5-Cl-phenyl)CH₂CH₂—; furanyl-CH₂CH₂—, thienyl-CH₂CH₂—,pyridyl-CH₂CH₂—, 1-imidazolyl-CH₂CH₂—, oxazolyl-CH₂CH₂—,isoxazolyl-CH₂CH₂—, 3,5-dimethylisoxazol-4-yl-CH₂CH₂—, phenyl-propyl-;benzyl-CH(NH₂)—, benzyl-CH(NHC(═O)—O-tBu)-, benzyloxy-CH₂—,pyrrolidin-2-yl-, or 3-t-butoxycarbonylpyrrolidin-2-yl-; R² is H ormethyl; R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CH₂CH₂CH₂CH₂CH₃,—CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH(CH₂CH₃)₂,—CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃, —CH═CH₂,—CH₂CH═CH₂, —CH₂CH₂CH═CH₂, —CH═CHCH₃, cis-CH₂CH═CH(CH₃),trans-CH₂CH═CH(CH₃), trans-CH₂CH═CH(C₆H₅), —CH₂CH═C(CH₃)₂,cis-CH₂CH═CHCH₂CH₃, trans-CH₂CH═CHCH₂CH₃, cis-CH₂CH₂CH═CH(CH₃),trans-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CHCH₂(C₆H₅), —C≡CH, —CH₂C≡CH,—CH₂C≡C(CH₃), —CH₂C≡C(C₆H₅), —CH₂CH₂C≡CH, —CH₂CH₂C≡C(CH₃),—CH₂CH₂C≡C(C₆H₅), —CH₂CH₂CH₂C≡CH, —CH₂CH₂CH₂C≡C(CH₃),—CH₂CH₂CH₂C≡C(C₆H₅), cyclopropyl-CH₂—, cyclobutyl-CH₂—,cyclopentyl-CH₂—, cyclohexyl-CH₂—, (2-CH₃-cyclopropyl)CH₂—,(3-CH₃-cyclobutyl)CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—, (2-CH₃-cyclopropyl)CH₂CH₂—,(3-CH₃-cyclobutyl)CH₂CH₂—, phenyl-CH₂—, (2-F-phenyl)CH₂—,(3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,2-furanyl-CH₂—, 3-furanyl-CH₂—, 2-thienyl-CH₂—, 3-thienyl-CH₂—,2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—, 1-imidazolyl-CH₂—,2-oxazolyl-CH₂—, 4-oxazolyl-CH₂—, 5-oxazolyl-CH₂—, 3-isoxazolyl-CH₂—,4-isoxazolyl-CH₂—, 5-isoxazolyl-CH₂—, phenyl-CH₂CH₂—,(2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—,furanyl-CH₂CH₂—, thienyl-CH₂CH₂—, pyridyl-CH₂CH₂—, 1-imidazolyl-CH₂CH₂—,oxazolyl-CH₂CH₂—, isoxazolyl-CH₂CH₂—; methoxy, ethoxy, propoxy, orbutoxy; R^(5a) is H; alternatively, R⁵ and R^(5a) may be combined toform cyclopentyl, cyclohexyl, or cycloheptyl; W is a bond, X is a bond;

Y is a bond, Z is H, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl,2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl,2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl,2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl,3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl,3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl,3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl,2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl, thienyl, pyridyl,N-oxide-pyridinyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl,1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, morpholino,N-piperinyl, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,(4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—,(4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,(2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—,(3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,(2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—,(3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,(3-Cl-4-F-phenyl)CH₂—, (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—,(4-MeO-phenyl)CH₂—, (2-PhO-phenyl)CH₂—, (3-PhO-phenyl)CH₂—,(4-PhO-phenyl)CH₂—, (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—,(4-Me-phenyl)CH₂—, (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—,4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—,(4-CF₃O-phenyl)CH₂—, (furanyl)CH₂—, (thienyl)CH₂—, (pyridyl)CH₂—,(2-Me-pyridyl)CH₂—, (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—,(1-imidazolyl)CH₂—, (oxazolyl)CH₂—, (isoxazolyl)CH₂—,(1-benzimidazolyl)CH₂—, (cyclopropyl)CH₂—, (cyclobutyl)CH₂—,(cyclopentyl)CH₂—, (cyclohexyl)CH₂—, (morpholino)CH₂—,(N-pipridinyl)CH₂—, phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—,(2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—,(2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—,(2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,(2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,(3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,(2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,(2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,(3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—,(3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—,(3-C-4-F-phenyl)CH₂CH₂—, (2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl)CH₂CH₂—,(4-MeO-phenyl)CH₂CH₂—, (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—,(4-Me-phenyl)CH₂CH₂—, (2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—,(4-MeS-phenyl)CH₂CH₂—, (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—,(4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—, (thienyl)CH₂CH₂—,(pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—,(4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—,(isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—, (cyclopropyl)CH₂CH₂—,(cyclobutyl)CH₂CH₂—, (cyclopentyl)CH₂CH₂—, (cyclohexyl)CH₂CH₂—,(morpholino)CH₂CH₂—, or (N-pipridinyl)CH₂CH₂— and R¹³, at eachoccurrence, is independently selected from H, MeO, F, and Cl.
 8. Acompound or pharmaceutically acceptable salt thereof, of Formula (Ib)

wherein: Ring B is

Q¹ is C₁-C₆ alkyl substituted with 0-3 R^(1a); C₂-C₆ alkenyl substitutedwith 0-3 R^(1a); C₂-C₆ alkynyl substituted with 0-3 R^(1a); C₃-C₁₀cycloalkyl substituted with 0-3 R^(1b); C₃-C₁₀ carbocycle substitutedwith 0-3 R^(1b); aryl substituted with 0-3 R^(1b); or 5 to 10 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 10 membered heterocycle issubstituted with 0-3 R^(1b); R^(1a), at each occurrence, isindependently selected from H, C₁-C₆ alkyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶,CF₃; C₃-C₁₀ carbocycle substituted with 0-3 R^(1b); C₆-C₁₀ arylsubstituted with 0-3 R^(1b); and 5 to 10 membered heterocycle containing1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, whereinsaid 5 to 10 membered heterocycle is substituted with 0-3 R^(1b);R^(1b), at each occurrence, is independently selected from H, OH, Cl, F,Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄haloalkyl-S—, and (C₁-C₆ alkyl)-O—C(═O)—; R⁵ is OR¹⁴; C₁-C₆ alkylsubstituted with 0-3 R^(5b); C₂-C₆ alkenyl substituted with 0-3 R^(5b);or C₂-C₆ alkynyl substituted with 0-3 R^(5b); R^(5a) is H, methyl,ethyl, propyl, butyl, or C₂-C₄ alkenyl; alternatively, R⁵ and R^(5a) maybe combined to form a C₄-C₇ cycloalkyl ring; R^(5b), at each occurrence,is independently selected from: H, methyl, ethyl, propyl, butyl, CF₃,OR¹⁴, Cl, F, Br, I, ═O, NR¹⁵R¹⁶, C₃-C₇ cycloalkyl substituted with 0-3R^(5c); C₃-C₇ carbocycle substituted with 0-3 R^(5c); phenyl substitutedwith 0-3 R^(5c); and 5 to 7 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 7 membered heterocycle is substituted with 0-3 R^(5c); R^(5c), ateach occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; W is —(CHR⁸)_(p)—; p is 0or 1; R⁸ is H, methyl, or ethyl; X is a bond; phenyl substituted with0-2 R^(Xb); C₅-C₆ cycloalkyl substituted with 0-3 R^(Xb); or 5 to 6membered heterocycle containing 1 to 3 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycleis substituted with 0-2 R^(Xb); R^(Xb), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; Y is a bond, —V—,—CH₂—V—, —V—CH₂—, or —CH₂—V—CH₂—; V is a bond, —C(═O)—, —O—, —S—,—S(═O)—, —S(═O)₂—, or —N(R¹⁹)—; Z is H, F, Cl, Br, C₁-C₄ alkylsubstituted with 0-2 R¹²; C₂-C₄ alkenyl substituted with 0-2 R¹²; C₂-C₄alkynyl substituted with 0-2 R¹²; aryl substituted with 0-4 R^(12b);C₃-C₆ carbocycle substituted with 0-4 R^(12b); or 5 to 6 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 6 membered heterocycle issubstituted with 0-3 R^(12b); R¹² at each occurrence, is independentlyselected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; C₆-C₁₀ arylsubstituted with 0-4 R^(12b); C₃-C₁₀ carbocycle substituted with 0-4R^(12b); or 5 to 10 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 10membered heterocycle is substituted with 0-3 R^(12b); R^(12b), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂,NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl-S—; R¹³,at each occurrence, is independently selected from H, OH, C₁-C₆ alkyl,C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; R¹⁴, at eachoccurrence, is independently selected from H, phenyl, benzyl, C₁-C₄alkyl, and C₂-C₄ alkoxyalkyl; R¹⁵, at each occurrence, is independentlyselected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, andphenethyl; R¹⁶, at each occurrence, is independently selected from H,OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl,CH₃CH₂C(═O)—, CH₃C(═O)—, CH₃CH₂OC(═O)—, CH₃OC(═O)—, CH₃CH₂S(═O)₂— andCH₃S(═O)₂—; R¹⁷ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl;R¹⁸, at each occurrence, is independently selected from H, methyl,ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and R¹⁹, at eachoccurrence, is independently selected from H, OH, methyl, ethyl, propyl,and butyl.
 9. A compound or pharmaceutically acceptable salt thereof, ofclaim 8 wherein: Q¹ is C₁-C₆ alkyl substituted with 0-3 R^(1a); C₂-C₆alkenyl substituted with 0-3 R^(1a); C₂-C₆ alkynyl substituted with 0-3R^(1a); C₃-C₆ cycloalkyl substituted with 0-3 R^(1b); phenyl substitutedwith 0-3 R^(1b); or 5 to 6 membered heterocycle containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5to 6 membered heterocycle is substituted with 0-3 R^(1b); R^(1a), ateach occurrence, is independently selected from H, methyl, ethyl,propyl, butyl, OR¹⁴, Cl, F, Br, I, NR¹⁵R¹⁶, CF₃; C₃-C₆ carbocyclesubstituted with 0-3 R^(1b); phenyl substituted with 0-3 R^(1b); and 5to 6 membered heterocycle containing 1 to 4 heteroatoms selected fromnitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycleis substituted with 0-3 R^(1b); R^(1b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl,methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy,(methyl)OC(═O)—, (ethyl)OC(═O)—, (propyl)OC(═O)—, and (butyl)OC(═O)—; R⁵is OR¹⁴; C₁-C₄ alkyl substituted with 0-1 R^(5b); C₂-C₄ alkenylsubstituted with 0-1 R^(5b); or C₂-C₄ alkynyl substituted with 0-1R^(5b); R^(5a) is H, methyl, ethyl, propyl, or butyl; alternatively, R⁵and R^(5a) may be combined to form a cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl ring; R^(5b), at each occurrence, isindependently selected from: H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴,Cl, F, ═O, NR¹⁵R¹⁶, C₃-C₇ cycloalkyl substituted with 0-3 R^(5c); C₃-C₇carbocycle substituted with 0-3 R^(5c); phenyl substituted with 0-3R^(5c); and 5 to 7 membered heterocycle containing 1 to 4 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 7membered heterocycle is substituted with 0-3 R^(5c); wherein said 5 to 7membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, andtetrazolyl; R^(5c), at each occurrence, is independently selected fromH, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, andC₁-C₂ haloalkoxy; W is a bond, —CH₂—, or —CH(CH₃)—; X is a bond; phenylsubstituted with 0-1 R^(Xb); C₅-C₆ cycloalkyl substituted with 0-1R^(Xb); or 5 to 6 membered heterocycle containing 1 to 3 heteroatomsselected from nitrogen, oxygen, and sulphur, wherein said 5 to 6membered heterocycle is substituted with 0-1 R^(Xb); wherein said 5 to 6membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl; R^(Xb), at eachoccurrence, is independently selected from H, OH, Cl, F, Br, NR¹⁵R¹⁶,CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl,methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; Y is abond, —V—, —V—CH₂—, or —CH₂V—; V is a bond, —C(═O)—, —O—, —S—, —S(═O)—,—S(═O)₂—, or —N(R¹⁹)—; Z is H, F, Cl, Br, C₁-C₄ alkyl substituted with0-2 R¹²; C₂-C₄ alkenyl substituted with 0-2 R¹²; C₂-C₄ alkynylsubstituted with 0-2 R¹²; aryl substituted with 0-4 R^(12b); C₃-C₆carbocycle substituted with 0-4 R^(12b); or 5 to 6 membered heterocyclecontaining 1 to 4 heteroatoms selected from nitrogen, oxygen, andsulphur, wherein said 5 to 6 membered heterocycle is substituted with0-3 R^(12b); R¹² at each occurrence, is independently selected from H,OH, Cl, F, Br, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂ haloalkoxy; phenyl substituted with 0-4 R^(12b);C₃-C₆ carbocycle substituted with 0-4 R^(12b); or 5 to 6 memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen,oxygen, and sulphur, wherein said 5 to 6 membered heterocycle issubstituted with 0-3 R^(12b); R^(12b), at each occurrence, isindependently selected from H, OH, Cl, F, Br, NR¹⁵R¹⁶, CF₃, acetyl,SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy,ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; R¹³, at eachoccurrence, is independently selected from H, OH, methyl, ethyl, propyl,butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NR¹⁵R¹⁶, and CF₃; R¹⁴,at each occurrence, is independently selected from H, phenyl, benzyl,methyl, ethyl, propyl, and butyl; R¹⁵, at each occurrence, isindependently selected from H, methyl, ethyl, propyl, or butyl; R¹⁶, ateach occurrence, is independently selected from H, OH, methyl, ethyl,propyl, butyl, phenyl, benzyl, and phenethyl; R¹⁸, at each occurrence,is independently selected from H, methyl, ethyl, propyl, butyl, phenyl,benzyl and, phenethyl; and R¹⁹, at each occurrence, is independentlyselected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl and,phenethyl.
 10. A compound or pharmaceutically acceptable salt thereof,of claim 9, wherein: Q¹ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₂CH₃, —CH(CH₃)₂, —CH(CH₃)CH₂CH₃,—CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃,—CH═CH₂, —CH₂CH═CH₂, —CH₂C(CH₃)═CH₂, —CH₂CH═C(CH₃)₂, —CH₂CH₂CH═CH₂,—CH₂CH₂C(CH₃)═CH₂, —CH₂CH₂CH═C(CH₃)₂, cis-CH₂CH═CH(CH₃),cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃), trans-CH₂CH₂CH═CH(CH₃);—C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃), cyclopropyl-, cyclobutyl-, cyclopentyl-,cyclohexyl-, cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—, phenyl-, 2-F-phenyl-,3-F-phenyl-, 4-F-phenyl-, 4-methoxyphenyl-, 4-ethoxyphenyl-,4-propoxyphenyl-, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,(4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—,(4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,(2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—,(3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,(2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—,(3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,(3-Cl-4-F-phenyl)CH₂—, 2-furanyl-CH₂—, 3-furanyl-CH₂—, 2-thienyl-CH₂—,3-thienyl-CH₂—, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—,1-imidazolyl-CH₂—, 2-oxazolyl-CH₂—, 4-oxazolyl-CH₂—, 5-oxazolyl-CH₂—,3-isoxazolyl-CH₂—, 4-isoxazolyl-CH₂—, 5-isoxazolyl-CH₂—, phenyl-CH₂CH₂—,(2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—,(2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—,(2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,(2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,(3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,(2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,(2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,(3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—,(3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—; furanyl-CH₂CH₂—,thienyl-CH₂CH₂—, pyridyl-CH₂CH₂—, 1-imidazolyl-CH₂CH₂—,oxazolyl-CH₂CH₂—, isoxazolyl-CH₂CH₂—, 3,5-dimethylisoxazol-4-yl-CH₂CH₂—,phenyl-propyl-; benzyl-CH(NH₂)—, benzyl-CH(NHC(═O)—O-tBu)-,benzyloxy-CH₂—, pyrrolidin-2-yl-, or 3-t-butoxycarbonylpyrrolidin-2-yl-;R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CH₂CH₂CH₂CH₂CH₃,—CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH(CH₂CH₃)₂,—CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CH₃, —CH═CH₂,—CH₂CH═CH₂, —CH₂CH₂CH═CH₂, —CH═CHCH₃, cis-CH₂CH═CH(CH₃),trans-CH₂CH═CH(CH₃), trans-CH₂CH═CH(C₆H₅), —CH₂CH═C(CH₃)₂,cis-CH₂CH═CHCH₂CH₃, trans-CH₂CH═CHCH₂CH₃, cis-CH₂CH₂CH═CH(CH₃),trans-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CHCH₂ (C₆H₅), —C≡CH, —CH₂C≡CH,—CH₂C≡C(CH₃), —CH₂C≡C(C₆H₅), —CH₂CH₂C≡CH, —CH₂CH₂C≡C(CH₃),—CH₂CH₂C≡C(C₆H₅), —CH₂CH₂CH₂C≡CH, —CH₂CH₂CH₂C≡C(CH₃),—CH₂CH₂CH₂C≡C(C₆H₅), cyclopropyl-CH₂—, cyclobutyl-CH₂—,cyclopentyl-CH₂—, cyclohexyl-CH₂—, (2-CH₃-cyclopropyl)CH₂—,(3-CH₃-cyclobutyl)CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—, (2-CH₃-cyclopropyl)CH₂CH₂—,(3-CH₃-cyclobutyl)CH₂CH₂—, phenyl-CH₂—, (2-F-phenyl)CH₂—,(3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,2-furanyl-CH₂—, 3-furanyl-CH₂—, 2-thienyl-CH₂—, 3-thienyl-CH₂—,2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—, 1-imidazolyl-CH₂—,2-oxazolyl-CH₂—, 4-oxazolyl-CH₂—, 5-oxazolyl-CH₂—, 3-isoxazolyl-CH₂—,4-isoxazolyl-CH₂—, 5-isoxazolyl-CH₂—, phenyl-CH₂CH₂—,(2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—,furanyl-CH₂CH₂—, thienyl-CH₂CH₂—, pyridyl-CH₂CH₂—, 1-imidazolyl-CH₂CH₂—,oxazolyl-CH₂CH₂—, isoxazolyl-CH₂CH₂—; methoxy, ethoxy, propoxy, orbutoxy; R^(5a) is H; alternatively, R⁵ and R^(5a) may be combined toform cyclopentyl, cyclohexyl, or cycloheptyl; W is a bond, —CH₂—, or—CH(CH₃)—; X is a bond;

Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; V is a bond, —C(═O)—, —O—, —S—,—S(═O)—, —S(═O)₂—, —NH—, or —N(CH₃)—; Z is H, F, Cl, Br, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-F-phenyl, 3-F-phenyl,4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl,2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl,3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl,2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl,3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl,4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl,3-MeS-phenyl, 4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl,furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl,1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, morpholino,N-piperinyl, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—,(4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—,(4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,(2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—,(3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,(2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—,(3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,(3-Cl-4-F-phenyl)CH₂—, (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—,(4-MeO-phenyl)CH₂—, (2-PhO-phenyl)CH₂—, (3-PhO-phenyl)CH₂—,(4-PhO-phenyl)CH₂—, (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—,(4-Me-phenyl)CH₂—, (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—,4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—,(4-CF₃O-phenyl)CH₂—, (furanyl)CH₂—, (thienyl)CH₂—, (pyridyl)CH₂—,(2-Me-pyridyl)CH₂—, (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—,(1-imidazolyl)CH₂—, (oxazolyl)CH₂—, (isoxazolyl)CH₂—,(1-benzimidazolyl)CH₂—, (cyclopropyl)CH₂—, (cyclobutyl)CH₂—,(cyclopentyl)CH₂—, (cyclohexyl)CH₂—, (morpholino)CH₂—,(N-pipridinyl)CH₂—, phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—,(2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—,(2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—,(2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,(2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,(3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,(2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,(2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,(3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—, (3-Cl-4-F-phenyl) CH₂CH₂—,(2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—,(2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—, (4-Me-phenyl)CH₂CH₂—,(2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—,(2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—, (4-CF₃O-phenyl)CH₂CH₂—,(furanyl)CH₂CH₂—, (thienyl)CH₂CH₂—, (pyridyl)CH₂CH₂—,(2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—, (4-Me-pyridyl)CH₂CH₂—,(imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—, (isoxazolyl)CH₂CH₂—,(benzimidazolyl)CH₂CH₂—, (cyclopropyl)CH₂CH₂—, (cyclobutyl)CH₂CH₂—,(cyclopentyl)CH₂CH₂—, (cyclohexyl)CH₂CH₂—, (morpholino)CH₂CH₂—, or(N-pipridinyl)CH₂CH₂—; and R¹³, at each occurrence, is independentlyselected from H, MeO, F, and Cl.
 11. A pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt thereof, ofclaim 1; and a pharmaceutically acceptable carrier.
 12. A method for thetreatment of Alzheimer's Disease comprising administering to a host inneed of such treatment a therapeutically effective amount of a compoundof claim
 1. 13. A pharmaceutical composition comprising a compound orpharmaceutically acceptable salt thereof, of claim 2 and apharmaceutically acceptable carrier.
 14. A pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt thereof, ofclaim 3 and a pharmaceutically acceptable carrier.
 15. A pharmaceuticalcomposition comprising a compound or pharmaceutically acceptable saltthereof, of claim 4 and a pharmaceutically acceptable carrier.
 16. Apharmaceutical composition comprising a compound or pharmaceuticallyacceptable salt thereof, of claim 5 and a pharmaceutically acceptablecarrier.
 17. A pharmaceutical composition comprising a compound orpharmaceutically acceptable salt thereof, of claim 6 and apharmaceutically acceptable carrier.
 18. A pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt thereof, ofclaim 7 and a pharmaceutically acceptable carrier.
 19. A pharmaceuticalcomposition comprising a compound or pharmaceutically acceptable saltthereof, of claim 8 and a pharmaceutically acceptable carrier.
 20. Apharmaceutical composition comprising a compound or pharmaceuticallyacceptable salt thereof, of claim 9 and a pharmaceutically acceptablecarrier.
 21. A pharmaceutical composition comprising a compound orpharmaceutically acceptable salt thereof, of claim 10 and apharmaceutically acceptable carrier.
 22. A method for treatment ofAlzheimer's Disease comprising administering to a host in need of suchtreatment a therapeutically effective amount of a compound orpharmaceutically acceptable salt thereof, of claim
 2. 23. A method fortreatment of Alzheimer's Disease comprising administering to a host inneed of such treatment a therapeutically effective amount of a compoundor pharmaceutically acceptable salt thereof, of claim
 3. 24. A methodfor treatment of Alzheimer's Disease comprising administering to a hostin need of such treatment a therapeutically effective amount of acompound or pharmaceutically acceptable salt thereof, of claim
 4. 25. Amethod for treatment of Alzheimer's Disease comprising administering toa host in need of such treatment a therapeutically effective amount of acompound or pharmaceutically acceptable salt thereof, of claim
 5. 26. Amethod for treatment of Alzheimer's Disease comprising administering toa host in need of such treatment a therapeutically effective amount of acompound or pharmaceutically acceptable salt thereof, of claim
 6. 27. Amethod for treatment of Alzheimer's Disease comprising administering toa host in need of such treatment a therapeutically effective amount of acompound or pharmaceutically acceptable salt thereof, of claim
 7. 28. Amethod for treatment of Alzheimer's Disease comprising administering toa host in need of such treatment a therapeutically effective amount of acompound or pharmaceutically acceptable salt thereof, of claim
 8. 29. Amethod for treatment of Alzheimer's Disease comprising administering toa host in need of such treatment a therapeutically effective amount of acompound or pharmaceutically acceptable salt thereof of claim
 9. 30. Amethod for treatment of Alzheimer's Disease comprising administering toa host in need of such treatment a therapeutically effective amount of acompound or pharmaceutically acceptable salt thereof, of claim 10.